WO2011005842A1 - Anti-rsv compounds - Google Patents

Abstract

The present invention relates to anti-RSV compounds of Formula (I) and methods for use of the compounds in the treatment and prevention of RSV infection.

Description

Anti-RSV Compounds

The present invention relates to novel compounds that are used for inhibiting respiratory syncytial virus (RSV) activities and for treating RSV infection in a subject.

The present invention provides a compound of Formula I:

Formula

A is ary! or heteroary!;

Ri is alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocyclyi, cycloalkyl, said

heterocyclyi is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxyl, haloalkyl, alkoxy, alkyl, alkoxy- alkyl-,hydroxyl-alkyl-, CN, alkyl-NH-,,; said aryl or heteroaryl is optionally substituted by one to three substituents independentiy selected from the group consisting of halo, cyano, nitro, hydroxyl, alkyl, aikoxy, alkyl-NH-, with the proviso that when A is aryl, Ri is not unsubstituted aryl;

R₂ is hydrogen, alky!, aikoxy, amino, alkyl-NH-, CN, a!kyl-SO₂~, or halo;

R₃ is hydrogen, aikyl, heterocyciyl, heteroaryl, heteroaryl-alkyl-, or cycloalkyl, said alky! is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)--, halo, hydroxyl, NH₂-SO₂-, alkoxy-alkyl-, heterocyciyl; aryl, heteroary!, CN, alkyl-NH-

R₄ is hydrogen, or aikyl; or haloaikyi

R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring;

R₅ is hydrogen, aikyl, aikoxy, haloaikyi, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

In one embodiment, according to Formuia I₁ A is C₆-Ci₀ aryl, or monocyclic 6- membered heteroaryl. in one embodiment, according to Formula I, A is monocyclic 5-membered heteroaryl or bicyclic 8- to 10-membered heteroaryl.

In one embodiment, according to Formula I, A is a monocyclic 5-membered heteroaryl; Ri is aikyl, or aryl; R₂ is hydrogen, or aikyl; R₃ is cycloalkyl, or aikyl; R₄ is hydrogen; R₅ is hydrogen, or halo. Preferably, A is thienyi or pyrazolyl group.

In one embodiment, according to Formula I, A is a bicyclic 8- to 10-membered heteroaryl; Ri is aikyl, or hydrogen; R₂ is hydrogen, or aikyl; R₃ is cycioalkyl, or aikyl; R₄ is hydrogen; R₅ is hydrogen, or halo. Preferably, A is indolyl, indazolyl, or quinoxalinyl group. In one embodiment, the present invention provides a compound of Formuia

IA:

Formula IA wherein X, Y and Z are independently N or CH.

Ri is alkyi, alkoxy, haloalkyl, aryl, heteroaryl, heterocyclyl, said heterocyclyl is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxyl, haloalkyl, alkoxy, alkyl, alkoxy-alkyl-, and hydroxyl-alkyl— , said aryi is optionally substituted by one to two substituents independently selected from the group consisting of halo, cyano, nitro and hydroxyl, with the proviso that when X and Y are simultaneously CH, Ri is not unsubstituted aryl;

R₂ is hydrogen, alky!, alkoxy, or halo; R₃ is hydrogen, alkyl, heterocyctyl, heteroaryl, heteroaryl-aikyl--, or cycloalkyl, said aikyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, hydroxyl, NH₂-SO₂-, alkoxy-alkyl--, and heterocyclyl;

R₄ is hydrogen, or alkyl; R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring;

R₅ is hydrogen, alkyl, aikoxy, haloalkyl, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers. In one embodiment, according to Formula IA, X and Z are CH, Y is N.

In one embodiment, according to Formula IA₁ X, Y and Z are CH. In one embodiment, according to Formula IA₁ X and Z are N, Y is CH.

In one embodiment, according to Formula IA, X and Z are CH; Y is N; Ri is haloalkyl, or heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl--, alkyl, haloalkyl, or hydroxyl-alkyl-; R₂ is hydrogen; R₃ is hydrogen, aikyl, heteroaryl, heteroaryl-alkyl--, or cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)--, halo, hydroxyl, NH₂-SO₂-, alkoxy-alkyl-, and heterocyclyl; R₄ is hydrogen, or alkyl; R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7- membered ring; R₅ is hydrogen, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers. Preferably, Ri is (Ci-C^haloalkyl, or 4- to 7-membered heterocyclyl, said heterocyciyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, (CrC₄)a!koxy-(Ci-C₄)a!kyl~, (C_rC₄)alkyl, (C_r

C₄)haloalkyl, or hydroxyl-(C_rC₄)alkyl-; R₃ is hydrogen, (Ci-C₄)alkyl, 5- to 9- membered heteroaryi, 5- to 9-membered heteroaryl-(Ci-C₄)a!kyi— , or (C₃- C₇)cycioalkyl, said alky! is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, hydroxyl, NH₂-SO₂-, (CrC₄)alkoxy-(Ci- C₄)a!kyl--, and 4- to 7-membered heterocyclyi; R₄ is hydrogen, or (CrC₄)alkyl.

In one embodiment, X, Y and Z are CH; R₁ is alky!, alkoxy, or heteroaryl; R₂ is hydrogen, or alkoxy; R₃ is cycloalkyl; R₄ and R₅ are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers. Preferably, Ri is (CrC₄)alkyl, (Ci-C₄)alkoxy, or 5- to 9-membered heteroaryl; R₂ is hydrogen, or (C_rC₄)alkoxy; R₃ is (C3-C₇)cyc!oalkyl; R₄ and R₅ are hydrogen.

In one embodiment, X and Z are N, Y is CH; Ri is alkyl, aikoxy, or heteocyclyl; R₂ is alky!; R₃ is cycloalkyl; R₄ and R₅ are hydrogen; or a pharmaceutically

acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

In one embodiment, the present invention provides a compound of Formula

IB:

wherein R-i is haloalkyl, or heterocyclyi, said heterocyclyi is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-aikyl-, alkyl, haioalkyl, or hydroxyl-alky!-; R₃ is hydrogen, alky!, heterocyclyl, heteroaryl, heteroaryl-alkyl-, or cycloalkyl, said aikyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, or hydroxy!; R₄ is hydrogen; R₅ is hydrogen, or haio; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optica! isomers. In one embodiment, according to Formula IB₁ Ri is heterocyclyl that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alky!— , aikyl, haioalkyl, or hydroxyl-alkyl-. Preferably, Ri is 4- to 5-membered heterocyclyl, or 7-membered heterocyclyl.

Preferably, Ri is 4- to 5-membered heterocyclyl, or 7-membered heterocyclyl

Preferably, Ri is pyrrolidinyl, azetidinyl, or 2-oxa-6-spiro[3,3]heptan-6-yL in one embodiment, according to Formula IB, R₃ is hydrogen, alky!, cycloalkyl, heteroaryl, heteroaryl-alkyl-, or heterocyclyl, said aikyl is optionally substituted by one substituent selected from the group consisting of halo, or hydroxyl. Preferably, R₃ is, hydrogen, (C₃-C₇)cycloalkyl, 4- to 7-membered heterocyciyl, or (C_rC₄)alkyl that is optionally substituted by one halo group. Preferably, R₃ is cyclopropyl. in one embodiment, according to Formula IB, Ri is 4- to 7-membered heterocyclyl that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxy!, (Ci-C₄)alkoxy-(Ci-C₄)a!kyl~, (CrC₄)alkyl, (C_rC₄)haloalkyl_t or hydroxyl-(C_rC₄)aikyl-; R₃ is hydrogen, (C₃- C₇)cycloalkyl, 4- to 7-membered heterocyciyl, or (Ci-C₄)alkyi that is optionally substituted by one halo group or one 5- to 6-membered heteroaryl group; R₄ and R₅ are hydrogen; or a pharmaceutically acceptable salt thereof; or an optica! isomer thereof, or a mixture of optica! isomers.

In one embodiment, according to Formula IB₁ R₁ is pyrrolidinyl; R₃ is hydrogen, cyclopropyl, or (Ci-C₄)alkyl that is optionally substituted by one halo group or one 5- to 6-membered heteroaryl group; R₄ and R₅ are hydrogen; or a

pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers. In one embodiment, according to Formula IB, Ri is azetidiny! or 2-oxa-6- spiro[3,3]heptan-6-yl; R₃ is cyclopropyl; R₄ and R₅ are hydrogen; or a

pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

In one embodiment, the present invention provides a compound of Formula IC:

wherein

R₁ is cycloalkyiamino, aikyl, haloalkyl, heteroaryl, or aryl that is substituted with one halogen group;

R₂ is hydrogen; and

X and Y are independently N or CH; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers. Alternatively, Ri is alky!, R2 is alkoxy, and X and Y are both CH; or a

pharmaceutically acceptable salt thereof.

Preferably, the present invention provides the compound of formula I, wherein R₁ is (4 to 6-membered)-cycloalkyiamino, (C₁-C₄) alkyi, (C₁-C₄) haloalkyl, phenyl, or thiophene, said phenyl being optionally substituted with one fluorine group; R₂ is hydrogen; and X and Y are independently N or CH; or a pharmaceuticaily acceptable salt thereof.

Preferably, the present invention provides the compound of formula I, wherein R₁ is (CrC₄) alkyl; R₂ is (CrC₄) aikoxy; and X and Y are both CH; or a

pharmaceutically acceptable salt thereof.

Also preferably, the present invention provides the compound of formula I, or a pharmaceutically acceptable salt, or an optical isomer thereof, or a mixture of optical isomers, wherein the compound is represented by the following structures:

- 14-

-15-

- 16-

-18-

and

For purposes of interpreting this specification, the following definitions wiil apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

As used herein, the term "alkyl" refers to a saturated branched or unbranched hydrocarbon moiety. Preferably the aikyl comprises 1 to 20 carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, /i-propyl, /so-propyi, n-butyl, sec-butyl, /so-butyl, ferf-butyl, n-pentyl, isopentyl, neopentyl, /i-hexyl, 3-methylhexyi, 2,2- dimethylpentyl, 2,3-dimethylpentyi, π-heptyi, n-octyl, π-nonyl, n- decyl and the like. When an alkyl group includes one or more unsaturated bonds, it may be referred to as an alkeny! (double bond) or an alkynyl (triple bond) group. Furthermore, when an alkyl group is linked to an aryl group (defined below), it may be referred to as an "arylalkyl" group.

As used herein, the term "alkoxy" refers to alkyl-O-, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tø/t-butoxy, pentyloxy, hexyioxy, cyciopropyioxy-, cyclohexyloxy- and the like, As used herein, the term lower aikoxy" refers to the alkoxy groups having 1-7 carbons and preferably 1-4 carbons. The term "aryl" refers to monocyclic or bicyciic aromatic hydrocarbon groups having 6-16 carbon atoms in the ring portion. Preferably, the aryl is a (C₆-Ci₀) aryl. Non-limiting examples include phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as optionally substituted aikyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, aikyt-C(O)-O- -, aryl-O--, heteroaryl-O--, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, aϊkyl-O-C(O)--, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocycloalkyl and the like.

Furthermore, the term "aryl" as used herein, also refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covaleπtly, or linked to a common group such as a methylene or ethylene moiety. The common linking group also can be a carbonyl as in benzophenone or oxygen as in diphenylether or nitrogen as in diphenylamine.

As used herein, the term "cycloalkyl" refers to optionally substituted saturated or unsaturated monocyclic, bicyciic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamtno, thiol, alkylthio, nitro, cyano, carboxy, aikoxycarbonyl, sulfonyl, suifonamido, suifamoyl, heterocyclyl and the like. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyt and the like. Exemplary bicyciic hydrocarbon groups include bornyl, indyl,

hexahydroindyi, tetrahydronaphthyl, decahydronaphthyl, bicycie[2.1.1]hexyl;

bicycle[2.2. Ijheptyl, bicycle[2.2. Ijheptenyl, 6,6- dim ethyl bicycio[3. 1.1]heptyl, 2,6,6- thmethylbicyc!o[3. 1.1]heptyi, bicycle[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

As used herein, the term "cycloalkylamino" refers to a cycloalkyl group as defined herein wherein one carbon atom on the ring is substituted with a nitrogen atom and the cycloalkylamino group is attached via the nitrogen atom to the dependent molecule.

As used herein, the term "haloalkyl" refers to an alkyi as defined herein, that is substituted by one or more haio groups as defined herein. Preferably the haloalky! can be monohaioalkyl, dihaloalkyl or poiyhaloalkyl including perhaloalkyl. A

monohaloalkyl can have one iodo, bromo, chloro or fluoro within the alkyl group. Dihaloaikyl and poiyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Preferably, the

polyhaioaikyl contains up to 12, 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non- limiting examples of haloaikyl include fluoromethyl, difluoromethyi, trifluoromethyi, chloromethyl, dichioromethyl, trichioromethyi, pentafluoroethyl, heptafluoropropyl, difluorochioromethyl, dichiorofluoromethyl, difiuoroethyl, difluoropropyl, dichioroethyi and dichioropropyl. A perhaloalkyl refers to an alkyi having all hydrogen atoms replaced with halo atoms. As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicycfic- or fused pofycyclic-ring system, having 1 to 8 heteroatoms selected from N, O or S. Preferably the heteroaryl is mono-, bi-, or tricyclic, more preferably mono- or bicyclic. Preferably, the heteroaryi is a 5-10 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, A-, or 5- imidazolyi, 3-, 4-, or 5- pyrazolyl, 2-, 3-, 4-, 5-, or 6-pyhdinyt, 2~, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1 ,2,4-triazolyl, 4- or 5-1 ,2, 3-triazolyl, tetrazolyi, 2-, 4-, or 6-triazinyi, 2-, 3-, or 4-pyridyl, 3- or A- pyridazinyl, 3-, 4- , or 5-pyrazinyl, 2-pyrazinyl, 2-, A-, or 5-pyrimidinyI, 4- or 5-1 -oxa- 2,3-diazoIyI, 3- or 5-1 -oxa-2,4-diazolyl, 3- or 4-1-oxa-2,5-diazolyi, 2- or 5-1-oxa-3,4- diazolyl, 4- or 5-1-thia-2,3-diazolyl, 3- or 5-1-thia-2,4-diazolyl, 3- or 4-1-thia-2,5- diazolyl, 2- or 5-1-thia-3,4-diazolyl, and the like.

The term "heteroaryl" also refers to a group in which a heteroaromatic ring is fused to one or more aryl, partially unsaturated cycloaiiphatic, or partially unsaturated heterocycloalkyl rings, where the radical or point of attachment is on the

heteroaromatic ring. Nonlimiting examples include but are not limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8- indolizinyl, 1 -, 3-, 4-, 5-, 6-, or 7-isoindolyf, 2-, 3-, A-, 5-, 6-, or 7-indolyl, 2- , 3-, A-, 5-, 6-, or 7-indazolyI, 2-, A-, 5-, 6-, 7-, or 8- purinyl, 1-, 2-, 3-, A-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 1-, or 8-quinoiiyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoqutnoltyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyi, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyi, 2-, 4-, 6-, or 7-pteridinyi, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 1-, or 8-carbzaolyl, 1-, 3-, A-, 5- , 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyi, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyi, 1 -, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, A-, 5-, 6- , 8-, 9-, or 10-phenathrolinyl, 1-, 2- , 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyi, 1 -, 2-, 3-, A-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, A-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10- benzisoqinoliπyl, 2-, 3-, A-, or thieno[2,3- b]furanyi, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -, or 11-7H-pyrazino[2,3-c]carbazoiyi,2-, 3-, 5-, 6- , or 7-2H- furo[3,2-b]-pyranyl, 2-, 3-, A-, S-, 7-, or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1 H-pyrazolo[4,3-d]-oxazolyl, 2-, A-, or 54H-imidazo[4,5-d] thiazolyl, 3-, 5-, or 8- pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6- imidazo[2,1-b] thiazolyi, 1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnoliny1, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3- φarbazolyi, 2-, 3-, 6-, or 7-imidazo[1 ,2-b][1 ,2,4]triazinyl, 7-benzo[b]thienyl, 2-, A-, 5- , 6-, or 7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, A-, A-, 5-, 6-, or 7- benzothiazolyl, 1-, 2-, A-, 5-, 6-, 7-, 8-, or 9- benzoxapinyj, 2-, A-, 5-, 6-, 7-, or 8- benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, 11 -1 H-ρyrroio[1 ,2-b][2]benzazapinyi, benzo[b]furanyl, 2~, 3-, 5-, 6-, 7- or 8-quinoxalinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-indenyl, 1- , 2-, 3-, A-, 5-, 6-, 7-, or 8-azulenyl, 1-, 2-, 3-, A-, 5-, 6-, 7-, 8-, or 9-fluorenyl, benzothiphenyl, benzimidazoiyl, indazolyl, benzotriazoiyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyi, pyrrolo[3,2-b]pyridinyl, pyrroio[1 ,5- ajpyridinyl, pyrrolo[1 ,5-b]pyridinyi, imidazo[4,5-b3pyridiny!, imidazo[4,5-c]pyridinyl, imidazo[4,3-d]pyridinyl, imidazo[4,3-c]pyridinyl, imidazo[1 ,2-a]pyπdinyl, imidazo[1 ,5- a]pyridinyl, pyrazolo[1 ,5-a]pyridinyl, pyrrolo[1 ,2-b]pyridazinyl, thienopyrimidinyl, isoqutnoiinyl, 1 ,8-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrirnidinyl, pyrido[2,3-d]pyrimidinyi, pyπdo[2,3-b]pyrimidinyl, pyrido[3,4- b]pyrimidinyi, pyrimido[5,4-d]pyrimidinyl, pyraziπop^-bjpyraziny!, or pyrimido[4,5- d]pyrimidinyl. Typical fused heteroaryl groups include, but are not limited to 2-, 3-, A- , 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, A-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, A-, 5-, 6-, or 7- indolyl, 2-, 3-, A-, 5-, 6-, or 7-benzo[b]thieπyl, 2-, 4-, 5- , 6-, or 7-benzoxazolyl, 2-, 4~, 5-, 6-, or 7-benzimidazolyi, 2-, 4-, 5-, 6-, or 7-benzothiazolyl, 2-, 3-, 4-, 5-, 6-, or 7-.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic.

As used herein, the term "heterocycloalky!" or "heterocyclyl" refers to an optionally substituted, saturated or partially unsaturated, nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3, or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may also optionally be oxidized. The heterocyclic group may be attached at a heteroatom or a carbon atom. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1 , then these heteroatoms are not adjacent to one another. The bicyciic and tricyclic heterocyclyl groups can be fused or spiro rings or ring groups. Exemplary monocyclic heterocyclic groups include oxetanyl, thiatanyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyi, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyrazolyl, tetrahydropyrazolyl, dihydropyridinyl,

tetrahydropyridinyi, dihydrothiopyranyl, tetrahydrothipyranyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, dihydrothiopyranyl, tetrah yd roth io pyranyl, ptperidinyl, piperazinyi, morphoiinyl, azepinyl, dihydroazepinyl, tetrahydroazepinyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, oxepanyl, thiepanyl, dihyrothiepinyi, tetrahydrothiepinyl, dihydrooxepinyl, tetrahydrooxepinyl, 1 ,4-dioxanyi, 1 ,4-oxathianyl, morphoiinyl, oxazolyl, oxazolidinyl, isoxazolinyi, A- ptperidony!, isoxazoiinyi, isoxazolyl, 1 ,4-azathianyl, 1 ,4-oxathiepany!, 1 ,4- oxaazepanyl, 1 ,4-dithiepanyi, 1 ,4-thieaxepanyl, 1 ,4-diazepanyl, tropanyl, 3,4-dihydro- 2H-pyranyl, 5,6-dihydro-2H~pyranyi, thiazolidinyl, thiamorpholinyl, thiamorpholiny! sulfoxide, thiamorphoiinyl suifone, 1 ,3-dioxolane and tetrahydro-1 ,1 -dioxothienyl, 1 ,1 ,4-trioxo-1 ,2,5-thiadiazolidin-2-yf, pyrazolinyl, and the like.

Exemplary bicyclic heterocyclic groups include but are not limited to,

dihydroϊndolyl, quinuctidinyl, tetrahydroquinolinyl, decahydroquinolinyi, 2-oxa-6- azaspiro[3,3]heptan-6-yi, tetrahydroisoquinoiinyl, decahydroisoquinoiiny!,

dihydroisoindolyl, indoiinyl, norboranyl, adamantanyl, and the like.

As used herein, the term "carbamoyl" refers to H₂NC(O)-, alkyl-NHC(O)-, (alkyl)₂NC(O)-, aryi-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-,

alkyl(heteroaryl)-NC(O)-, aryl-alkyl-NHC(O)-, aikyl(aryl-alkyl)-NC(O)- and the like.

As used herein, the term "sulfonamido" refers to alkyl~S(O)₂-NH-, ary(-S(O)₂- NH-, aryi-alkyi-S(O)₂-NH-, heteroary!-S(O)₂-NH-, heteroaryl-alkyl-S(O)₂-NH-, aikyi- S(O)₂-N(alkyl)-, aryl-S(O)₂-N(alky!)-, aryl-alkyl-S(O)₂-N{alkyl)-, heteroaryl-S(O)₂- N(alkyl)-, heteroarrf-a!kyl-S(O)₂-N{alkyl)- and the like. As used herein, the term "sulfonyf" refers to R-SO₂--, wherein R is hydrogen, alkyi, aryl, hereoaryl, aryl-alkyl, heteroaryl-alkyl, ary!-O-, heteroaryl-O-, alkoxy, aryloxy, cycloalkyl, or heterocyciyi.

As used herein, the term "acyl" refers to a group R-C(O)- of from 1 to 10 carbon atoms of a straight, branched, or cyclic configuration or a combination thereof, attached to the parent structure through carbonyl functionality. Such group may be saturated or unsaturated, and aliphatic or aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, or aryl, or heteroaryl. Also preferably, one or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples inciude but are not limited to, acetyl, benzoyl, propionyl, isobutyryi, t- butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers to acyl containing one to four carbons. As used herein, the term "sulfamoyl" refers to H₂NS(O)₂-, alkyl-NHS(O)₂~, (aIkyi)₂NS(O)₂-, aryi-NHS(O)₂-, alkyl(aryl)-NS(O)₂-, (aryl)₂NS(O)₂-, heteroaryl- NHS(O)₂-, aralkyi-NHS(O)₂~, heteroaraikyl-NHS(O)₂- and the like.

As used herein, the term "aryloxy" refers to both an— O-ary! and an— O- heteroaryl group.

As used herein, the term "halo" or "halogen" refers to fiuoro, chloro, bromo, and iodo.

As used herein, the term "isomers" refers to different compounds that have the same molecular formula. Also as used herein, the term "an optical isomer" refers to any of the various stereo isomeric configurations which may exist for a given compound of the present invention and includes geometric isomers, it is understood that a substituent may be attached at a chiral center of a carbon atom. Therefore, the invention includes enantiomers, diastereomers or racemates of the compound. "Enantiomers" are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture where appropriate.

"Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold- Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycioalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. All tautomeric forms are also intended to be included.

As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto (e.g., phenol or hydroxyamic acid). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesuifonic acid, salicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the

ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethytamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutϊcaiiy acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods.

Generally, such salts can be prepared by reacting free acid forms of these

compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typicaily carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is herein incorporated by reference.

As used herein, the term "pharmaceutically acceptable carrier/excipient" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289- 1329, incorporated herein by reference). Except in so far as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, or ameliorate symptoms, slow or delay disease progression, or prevent a disease, etc.

As used herein, the term "subject" refers to an animal. Preferably, the animal is a mammal. A subject also refers to for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In a preferred embodiment, the subject is a human. As used herein, the term "a disorder" or "a disease" refers to any

derangement or abnormality of function; a morbid physical or mental state. See Borland's Illustrated Medical Dictionary, (W. B. Saunders Co. 27th ed. 1988). As used herein, the term "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disease, or a significant decrease in the baseline activity of a biological activity or process. In one embodiment this refers to the ability to block the production of infectious RSV virus particles. As used herein, the term "treating" or "treatment" of any disease or disorder refers to both therapeutic and prophylactic treatment. In one embodiment, therapeutic treatment refers to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, therapeutic treatment refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In yet another embodiment, therapeutic treatment refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom),

physiologically, (e.g., stabilization of a physical parameter), or both, in yet another embodiment, therapeutic treatment refers to delaying the onset or development or progression of the disease or disorder. Prophylactic treatment refers to reducing the likelihood of contracting disease or disorder, such as contracting the viral infection or developing an adverse condition in a subject when exposed to a virus. Preferably, the viral infection is reduced by about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80% or greater as compared to untreated controls. !t will be appreciated that the compounds of the present invention may have at least one asymmetric center. Therefore, the compounds are capable of existing in more than one stereoisomeric form. Any asymmetric carbon atom on the

compounds of the present invention can be present in the (R)-, (S)- or (R,S)- configuration, preferably in the (R)- or (S)-configuration. Therefore, the compounds of the present invention can be in the form of one of the possible isomers or mixtures thereof including racemates. Any resulting mixtures of isomers can be separated on the basis of the physicochemica! differences of the constituents, into the pure geometric or optica! isomers, diastereomers, racemates, for example, by known methods such as chromatography and/or fractional crystallization. The invention also provides isotopically enriched compounds that are compounds of formula I that comprise an enriched isotope at one or more positions in the compound.

The compounds of the present invention are either obtained in the free form or as a salt form thereof. When a basic group is present in the compounds of the present invention, the compounds can be converted into acid addition salts thereof, in particular, acid addition salts with the imidazoly! moiety of the structure, preferabiy pharmaceutically acceptable salts thereof. These are formed, with inorganic acids or organic acids. Suitable inorganic acids include but are not limited to, hydrochloric acid, sulfuric acid, a phosphoric or hydrohalic acid. Suitable organic acids include but are not limited to, carboxylic acids, such as (CrC₄) alkanecarboxylic acids which, for example, are unsubstituted or substituted by halogen, e.g., acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic, lactic, malic, tartaric or citric acid, such as amino acids, e.g., aspartic or glutamic acid, organic sulfonic acids, such as (Ci-C₄) aikylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonic acids which are unsubstituted or substituted, e.g., by halogen. Preferred are salts formed with hydrochloric acid, methanesuifonic acid and maleic acid.

When an acidic group is present in the compounds of the present invention, the compounds can be converted into salts with pharmaceutically acceptable bases. Such salts include alkali metal salts, like sodium, lithium and potassium salts;

alkaline earth metal salts, like calcium and magnesium salts; ammonium salts with organic bases, e.g., trimethytamine salts, diethylamine salts, tris (hydroxymethyi) methylamine salts, dicyclohexyiamine salts and Λ/-methyi-D-glucamine salts; salts with amino acids like argintne, lysine and the like. Salts may be formed using conventional methods, advantageously in the presence of an ethereal or alcoholic solvent, such as a lower alkanol. From the solutions of the latter, the salts may be precipitated with ethers, e.g., diethyl ether. Resulting salts may be converted into the free compounds by treatment with acids. These or other salts can also be used for purification of the compounds obtained. When both a basic group and an acid group are present in the same molecule, the compounds of the present invention can also form internal salts.

The compounds of the present invention are active RSV inhibitors, thus, have valuable pharmaceutical properties. The present invention therefore provides a method for treating a subject infected with RSV or prophylactic treatment of individuals susceptible to an RSV infection. The method comprises administering to said subject an effective amount of a compound of the present invention or a pharmaceuticaily acceptable carrier thereof. RSV is the leading cause of viral bronchiolitis and pneumonia in babies and children and is also responsible for much severe influenza-like illness in vulnerable adults including the elderly and

immunocompromised individuals RSV is prevalent among the general population during the winter months. It is a particularly serious risk amongst children who suffer from chronic lung disease, childen with congenital heart disease and children born pre-term . Accordingly, the compounds of the present invention are typically for use in treating a subject who is a child under two years of age, or a subject with asthma, COPD or immunodeficiency, or a subject who is elderly or in long term care facilities. In one embodiment, the compounds of the present invention are for use in treating a subject suffers from chronic lung disease. In addition, the compounds of the present invention are for use in preventing RSV infections. Additionally, the present invention provides (1 ) a compound of the present invention for use as a medicament; (2) the use of a compound of the present invention for the preparation of a medicament for treating RSV infection.

The compounds of Formula I, IA, IB and IC can be prepared by the

procedures described in the following sections. The invention also relates to methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of.Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1 , Ian T. Harrison and Shuyen Harrison, 1971 ; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vof. 5, Leroy G. 5 Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985),

Comprehensive Organic Synthesis. Selectivity. Strategy & Efficiency in Modern Organic Chemistry, fn 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing). A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures wil! be -100⁰C to 200'C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product. Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 ¹C), although for metal hydride reductions frequently the temperature is reduced to 0 'C to -100 'C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions. Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlied condensations reduced temperatures (0 ¹C to -100 ¹C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction byproducts and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable. The terms "treated",

"treating", "treatment", and the like, when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is

synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions common in the art of organic synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two. For example, treating indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01 M to 1 OM, typically O.IM to 1 M), temperatures (-100 ⁰C to 250 ⁰C, typically -78 ^0<C to 150 ⁰C₁ more 10 typically -78 ⁰C to 100 ⁰C, still more typically 0 ⁰C to 100 ⁰C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for "treating" in a given process, in particular, one of ordinary skili in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art. Modifications of each of the exemplary schemes and in the examples (hereafter "exemplary schemes") leads to various analogs of the specific exemplary materials produce. The above-cited citations describing suitable methods of organic synthesis are applicable to such modifications. In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified

(hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash

chromatography. Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, un reacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LlX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art wili apply techniques most likely to achieve the desired separation. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuiler, C. H., (1975) J Chromatogr., 113, 3) 283-15 302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1 ) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Under method (1 ), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-3-phenylethylamine (amphetamine), and the like with asymmetric

compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chirai carboxylic or sulfonic acids, such as camphorsuifonic acid, tartaric acid, mandelic acid, or Sactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chirai compound to form a diastereomeric pair (Eliel, E. and Wiien, S. (1994) 30 Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiornerically pure chirai derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene. A method of determining optica! purity involves making chirai esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, u-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob 11. (1982), J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinoiines (Eloye, T., WO 96/15111 ). A racemic mixture of two enantiomers can be separated by chromatography using a chirai stationary phase (Chirai Liquid Chromatography 10 (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J, of Chronatogr. 513:375-378). General Scheme of Making Compound of the Invention

Scheme 1 below outlines the general synthesis of the compounds in this invention. The benzazepin carboxyiate (R=H or R=Br) 1.1 was prepared according to procedures reported (Peesapati, V.; Lingaiah, N.; OPPIAK; Organic Preparations and Procedures International; English; 25; 5; 1993; 602 - 606; ISSN: 0030-4948 and Heterocycles, 2005, 66, p481-502). The carboxyiate functionality can be activated with a reagents such as Carbonyl diimidazole, benzotriazol-1-yi- oxytripyrrolidinophosphonium hexafluorophosphate, 2-(1 H-7-Azabenzotriazo!-1 -yi)- 1 ,1 ,3,3-tetramethyl uranium hexafluorophosphate methanaminium and the like to affect to formation of an amide bond upon reaction with a desired amine, to provide 1.2. The aniline product 1.2 is then reacted with a similarly activated carboxylic acid, preferably in the form of a carboxylic acid halide or the iike, to form intermediate 1.3 Reduction of the nitro compound can be accomplished with a wide range of reagents and conditions, such a low vaient metafs (Pd₁ Fe, Zn) in the absence or presence of hydrogen or other reducing agents known in the literature to provide aniline 1.4 The third amide bond to prepare compound 1.5 is then introduced in a similar fashion as in the preparation of intermediate 1.3 Some example compounds 1 5 can then be further manipulated through Installation of additional groups, e g amines to generate, for example 1.6. This can be accomplished either via a SN-1 (Ar)-type of reaction (heating in the presence of the desired amine in a polar protjc or aprotic solvent) or via a transition metal catalyzed reaction (see Buchwaid-, Uilman-type couplings or the similar)

Scheme 1

1.3 1.4

1 6 1 5 In another aspect, the present invention provides a pharmaceutical

composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as intravenous administration, oral administration, parenteral administration, an intranasal administration, an intrabronchiai

administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form including capsules, tablets, pills, granules, powders or suppositories, or in a liquid form including solutions, suspensions or emulsions. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifers and buffers etc.

The pharmaceutical compositions contain a therapeutically effective amount of a compound of the invention as defined above, either alone or in combination with one, two or three or more therapeutic agents, e.g., each at an effective therapeutic dose as reported in the art. In one embodiment, the compound of the present invention can be used in combination with an anti-inflammatory agent. Non-limiting examples of such anti-inflammatory agent include for example, salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, oisalazine; sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, toimetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meioxicam,

ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesuiide; leukotriene antagonists including, but not limited to, zileuton, aurothioglucose, gold sodium thiomalate and auranofin; and other anti-inflammatory agents including, but not limited to, colchicine, allopurinoi, probenecid, sulfinpyrazone and benzbromarone.

In one embodiment, the compound of the present invention can be used in combination with another anti-viral agent, such as an anti-influenza agent. Non- limiting examples of such anti-viral agent include nucleoside analogs, such as zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, and ribavirin, as well as foscarnet, amantadine, rimantadine, saquinavir, indinavir, ritonavir, and the aipha-interferons. Additionally, another anti-viral agent can function on a different target moiecule involved in viral replication, or prevent or reduce the occurrence of viral resistance.

In one embodiment, the compound of the present invention can be used in combination with another anti-RSV agent, e.g., nucleoside analogs such as

Ribavarin, monoclonal antibodies such as Synagis® and antisense oligonucleotides or other small molecule inhibitors of RSV. in one embodiment, the compound of the present invention can be used in combination with supportive care, such as of humidified oxygen and respiratory assistance, etc.

A compound of the present invention may be administered either

simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.

Furthermore, the combinations as described above can be administered to a subject via simultaneous, separate or sequential administration (use). Simultaneous administration (use) can take place in the form of one fixed combination with two or three or more active ingredients, or by simultaneously administering two or three or more compounds that are formulated independently. Sequential administration(use) preferably means administration of one (or more) compounds or active ingredients of a combination at one time point, other compounds or active ingredients at a different time point, that is, in a chronically staggered manner, preferably such that the combination shows more efficiency than the single compounds administered independently (especially showing synergism). Separate administration (use) preferably means administration of the compounds or active ingredients of the combination independently of each other at different time points, preferably meaning that two, or three or more compounds are administered such that no overlap of measurable blood levels of both compounds are present in an overlapping manner (at the same time).

A!so combinations of two or three or more of sequential, separate and simultaneous administrations are possible, preferably such that the combination compound-drugs show a joint therapeutic effect that exceeds the effect found when the combination compound-drugs are used independently at time intervals so large that no mutual effect on their therapeutic efficiency can be found, a synergistic effect being especially preferred. The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1 000 mg of active ingredients for a subject of about 50- 70 kg, preferably about 5-500 mg of active ingredients, preferably about 0.1-100 mg of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. In another aspect, the activities of the compounds of the present invention can be assessed by the following assays.

Antiviral activity against RSV was determined using an in vitro cytoprotection assay in Hep2 cells, in this assay, compounds inhibiting the virus replication exhibit cytoprotective effect against the virus-induced ceil killing that can be quantified using a cell viability reagent. The method used is similar to methods previously described in Chapman J et at., "RSV604 a novel inhibitor of respiratory syncytial virus replication," Antimicrob Agents Chemother, 51 (9):3346-53 (2007). Hep2 cells were obtained from ATCC (Manassas, Vl) and maintained in MEM media supplemented with 10% fetal bovine serum and penicillin/streptomycin. Ceϋs were passaged twice a week and kept at subconfSuent stage. Commercial stock of RSV strain A2 (Advanced Biotechnologies, Columbia, MD) was titered before compound testing to determine the appropriate diiution of the virus stock that generates desirable cytopathic effect in Hep2 cells.

For antiviral tests, Hep2 cells were seeded into 96-weli plates 24 hours before the assay at a density of 3,000 cells/well. On a separete 96wei[ plate, tested compounds were serially diluted in cell culture media. Eight concentrations in 3-fold serial dilution increments were prepared for each tested compound and 100 uL/well of each dilution was transferred in duplicate onto plates with seeded Hep2 ceils. Subsequently, appropriate dilution of virus stock previously determined by titration was prepared in cell culture media and 100 uL/well was added to test plates containing cells and serially diluted compounds. Each plate incfuded three wells of infected untreated cells and three wells of uninfected cells that served as 0% and 100% virus inhibition control, respectively. Following the infection with RSV, testing plates were incubated for 4 days in a tissue culture incubator. After the incubation, RSV-induced cytopathic effect was determined using a Ceil TiterGlo reagent (Promega, Madison, Wl) foilowed by a luminescence read-out. The percentage inhibition was calculated for each tested concentration relative to the 0% and 100% inhibition controls and the EC50 value for each compound was determined by nonlinear regression as a concentration inhibiting the RSV-induced cytopathic effect by 50%. Ribavirin (purchased from Sigma, St. Louis, MO) was used as a positive control for antiviral activity. Cytotoxicity of tested compounds was determined in uninfected Hep2 cells in parallel with the antiviral activity using the cell viability reagent in a similar fashion as described before for other ceil types. See Cihlar, T. et al., "Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1 , and its orally bioavailable phosphonoamidate prodrug, GS-9131 ," Antimicrob Agents Chemother, 52{2):655-65 (2008).. Same protocol as for the determination of antiviral activity was used for the measurement of compound cytotoxicity except that the cells were not infected with RSV. instead, fresh eel! culture media (100 uL/weil) without the virus was added to tested plates with ceils and prediluted compounds. Cell were then incubated for 4 days followed by a cell viability test using CeilTiter GIo reagent and a luminescence read-out.

Untreated cell and cells treated with 50 ug/mL puromycin (Sigma, St. Louis, MO) were used as 100% and 0% cell viability control, respectively. The percent of cell viability was calculated for each tested compound concentration relative to the 0% and 100% controls and the CC50 value was determined by non-linear regression as a compound concentration reducing the cell viability by 50%.

Table 1 below shows that the compounds of the present invention inhibit RSV. Those compounds that show at least 60% greater inhibition have a EC50 value in the range of 1nM to 1 μM.

Table 1 Activities of Compounds

Abbreviations:

AcOH Acetic acid

ATCC American Type Culture Colection

C carbon

CH₃CN Acetonitriie

Cs₂CO₃ Cesium carbonate

CuI Copper iodide

DMAP dimethyfaminopyridine

DME Dimethoxyethane DIPEA diisopropyiethylamine

DMF dimethyfformamide

DMSO dimethylsulfoxide

dt doublet of triplets

Et ethyl

EtOAc Ethyl acetate

EtOH Ethanol

EDTA ethyienediaminetetraacetic acid

FAB fast atom bombardment

gem geminal

HATU 2-(1 H-7-Azabenzotriazoi-1-yl)~1 ,1 ,3_l3-tetramethy! uronium hexafluorophosphate Methanaminium

H₂ hydrogen gas

HBr hydrobromic acid

HCl hydrochloric acid

HPLC high performance liquid chromatography

HR high resolution

/ ipso

IR infrared spectroscopy

m multiplet

m meta

Me methyl

MeOH methanol

MeONa sodium methoxide

MS mass spectrometry

v wave number

N₂ nitrogen gas

NaHCO₃ sodium bicarbonate

NaOH sodium hydroxide

Na₂SO Sodium sulfate

NEt.₃ triethylamine NH₄OH ammonium hydroxide

NMR nuclear magnetic resonance

o ortho

p para

Pd Palladium

POCI₃ phosphorus oxychloride

Ph phenyl

PPh₃ triphenylphosphine

Py pyridyl

pyrr pyrrolyl

PyBroP Bromo-tris-pyrrolidino phosphoniumhexafluorophosphate q quartet

rei. relative

RT room temperature

s singlet

sat. saturated

sol. solution

t triplet

TBS te/f-butyldimethylsilyl

td triplet of doublets

TDA-1 tris[2-(2-methoxyethoxy)ethyi]amine

THF tetrahydrofuran

TFA trifluoroacetic acid

TPPTS sodium triphenylphosphine trtsulfonate

Tr trityl, triphenylmethyl

vie vicinal

HPLC high-pressure liquid chromatography

FBS fetal bovine serum

RPMI Royal Park Memorial Institute

TCA trichloroacetic acid

DIAD di-/sopropy! azaodicarboxylate PyBOP benzotriazoi-1-yl-oxytripyrroiidinophosphonium hexafluorophosphate DME dimethoxyethane

Examples

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

Intermediate A

The synthesis of intermediate A has been reported in Heterocycles, 2005, 66, p481- 502 and the method described below was based on the methods cited in this reference.

Step (i): 2-amino benzoic acid methyl ester (330 g) was dissolved in dichloromethane (1 L) and treated with pyridine and tosyl chloride (1.1 equiv). The mixture was stirred for 4 h and then washed with 1 N HCi (aq), followed by brine, dried over magnesium sulfate and concentrated. The residue was purified using silica gel chromatography to isolate the tosylated product. Step (ii): The tosylated product from step (i) (330 g) and potassium carbonate {520 g) were added to n-butanone (1.5 L) and treated with 4-bromobutyric acid ethyl ester (234 g). The mixture was stirred overnight and then concentrated under reduced pressure to give a crude product. The crude product was combined with another equivalent batch prepared in parallel. Step (ιιi) Crude product from step (n) (110Og) was added to toiuene (2 L) The mixture was treated with potassium t-butoxide (80Og) and stirred overnight The mixture was washed with 1 N HCl₁ followed by brine, and dryied over magnesium sulfate The organic solution was concentrated under reduced pressure to provide crude product

Step (iv) The crude product from step (in) was treated with 6N HCI (1 5 L) and AcOH (3 5 L) and stirred overnight The solution was washed with dichioromethane several times and the combined organic washes, washed with brine, dried over magnesium sulfate and concentrated The residue was chromatographed on silica gel to isolate intermediate A. intermediate B The preparation of intermediate B from Intermediate A was described in Organic Preparations and Procedures international, 1993, 25, p602-606

B1

Step (ι) POCI₃ (3 Oeq) was added to dry DMF and cooled in an ice bath Then the solution of compound A (2Og) in dry DMF was added into the mixture The mixture was stirred 1 h at room temperature and then refiuxed for 4 h The solution was added to ice water and saturated NaOAc aqueous solution added until the pH was neutral The mixture was extracted with ethyl acetate (500 mL x 3) The combined organic layers were washed with water, saturated NaHCO₃ solution, brine and dried over anhydrous NaSO₄. The mixture was filtered and concentrated under reduced pressure to provide 15 g of crude aldehyde A1 Step (ii) Metal sodium (2.0 eq based on A1) was dissolved in ethanol and cooled with an ice bath. Ethyl 2-mercaptoacetate was added to the solution and after 30 min, aldehyde A1 (15g) was added. The mixture was kept around O⁰C for 30 min and then refluxed for 3h. The mixture was cooled and 2N HCI aqueous solution added to adjust the pH to neutral. The mixture was then extracted with ethyl acetate and the organic layer, washed with water, saturated NaHCO₃ aqueous solution and saturated NaCI aqueous solution. The organic layer was dried over anhydrous NaSO₄, filtered and concentrated under reduced pressure to obtain a crude product (13g) which was moved to step (iii). Step (iii). The crude product from (ii) was dissolved in HBr in acetic acid (200 ml_) and boiled. Sulfuric acid (50%,v/v 100 mL) was added dropwise to the boiling mixture and heating continued for another 6h. The solution was cooled and concentrated to a crude residue. The residue was chromatographed over silica gel to provide intermediate B and intermediate B1.

¹H-NMR of B (DMSO, 300 MHz): δ 7.47 (d, J = 7.8 Hz₁ 1 H), 7.42 (s, 1 H), 6.97 (d, J = 8.1 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.72 (d, J = 8.4 Hz₅ 1 H), 6.60 (s, 1 H), 3.23-3.20 (m, 2H), 2.94-2.90 (m, 2H). ¹H-NMR of B1 (DMSO, 300 MHz): δ 7.51 (s, 1 H), 7.43 (s, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 6.61 (s, 1 H), 3.1 (m, 2H), 2.3 (m, 2H).

Intermediate C

B

To a solution of the acid B (2.5 g, 0.01 M) in dry pyridine (10 mL) was added cyclopropylamine (5.8 g, 0.1 Wl) and stirred under N₂. HATU (4.56 g, 0,012 M) was added portion wise and the solution stirred for 16 h at RT under N₂. Volatiles were removed under reduced pressure at 4O⁰C. The resulting residue was dissolved in

EtOAc (200 mL), the organic phase was washed 2x each with aqueous dilute

NaHCO₃, then H₂O followed by brine. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by silica gel column using 50% EtOAc in hexanes with a gradient from 50% to 100% to afford the product C

(2.73 g, 96%) as a yellow oil.

¹H-NMR (DMSO, 300 MHz): δ 8.63 (d, J = 4.5 Hz₁ 1 H)₁ 7.65 (t, J = 7.5 Hz, 1 H)₁ 7.30 (s, 1 H), 7.06 (t, J = 8.4 Hz, 1 H), 6.80 (t, J = 8.1 Hz, 1 H), 6.66 (d, J = 8.1 Hz₅ 1 H), 6.13 (S₁ 1 H), 3.42 (d, J = 5.1 Hz, 2H), 3.05 (d, J = 5.4 Hz, 2H), 2.89 (m, 1 H), 0.86 (m, 1 H), 0.63 (m, 1 H).

LC-MS m/z [M+H]⁺ C₁₆H₁₆N₂OS requires: 284.38. Found 285.02. HPLC Tr (min), purity %: 3.27, 95%. Intermediate D

C D

To a soSution of the amine C (1.5 g, 5.3 mM) in dry pyridine (10 imL) was added slowly a solution of p-nitrobenzoyl chloride (0.97 g, 5.3 mM) in CH₃CN (10 mL) and stirred under N₂ at RT for 2 h. Volatiles were removed under reduced pressure at 4O⁰C, the resulting residue dissolved in EtOAc (150 mL) and the organic phase was washed 2x each with aqueous dilute NaHCO₃, then H₂O followed by brine. Volatiles were removed under reduced pressure at 40⁰C, the resulting residue was purified by silica get column using 50% EtOAc in hexanes with a gradient from 50% to 100% EtOAc to afford intermediate D (1.47 g, 65%) as a yellow oil.

¹H-NMR (DlVlSO₁ 300 MHz): δ 8.50 (d, J = 4.2 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 2H)₁ 7.71 (d, J = 8.1 Hz, 1 H), 7.62 (s, 1 H), 7.23-7.16 (m, 3H), 7.00 (t, J = 8.4 Hz, 1 H), 6.87 (d, J = 7.5 Hz, 1 H), 4.83-4.78 (m, 1 H), 3.29-3.16 (m, 2H), 3.06-3.01 (m, 1 H), 2.79-2.73 (m, 1 H), 0.66-0.58 (m, 2H), 0.53-0.48 (m, 2H).

LCMS m/z [M÷Hf C₂₃Hi₉N₃O₄S requires: 433.11. Found 433.97 HPLC Tr (min), purity %; 3.88, 90% Intermediate E

Intermediate D <1.47g, 3.4 mM) was dissolved in hot EtOH (100 ml_) and 1 N HC! (5 mL) and cooled to RT. Pd/C (10%, 150 mg) was added under N₂ and H₂ bubbled through the suspension for 20 min. The suspension was then stirred under H₂ (balloon) for 2 h. After flushing with N₂, the suspension was filtered and the voSatiles removed under reduced pressure to afford intermediate E (1.32 g, 97%) as an off- white powder. ¹H-NMR (DMSO, 300 MHz): δ 8.53 (d, J = 3.9 Hz, 1 H)₁ 7.75 (cl, J - 7.8 Hz₅ 1 H), 7.64 (s, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 6.3 Hz, 1 H), 6.82-6.78 (m, 2H), 6.48 (d, J = 7.8 Hz, 2H), 3.22 (me, 4H), 2.79 (me, 1 H), 0.70-0.68 (m, 2H), 0.57-0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₂₃H_2IN₃O₂S requires: 403.14. Found 404.07

HPLC Tr (min), purity %: 3.18, 95%

Intermediate F

To a 50 ml_ fiask containing 20 mL of DMF was added 1 mL of oxaiy! chloride siowiy and stirred for 10 min at RT. 100 rng of 2-trifluoromethyl nicotinic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of 2-cyano-5- aminopyπdine was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was used directly in the next step. The nitrile was dissolved in methanol (10 mL) and water (10 mL). Sodium hydroxide (300mg) was added to the above solution and the solution heated at 70⁰C for 16 h. The reaction mixture was quenched with 1 N HCI (10 mL), and extracted with EtOAc four times (15 mL). Volatiles were evaporated and the intermediate F used without further purification in the next steps. intermediate G,

To a 50 mL flask containing 20 ml. of DMF was added 1 mL of oxalyi chloride slowly and stirred for 10 min at RT. The 4-bromo nicotinic acid (100mg) was added to 2 mL of the above solution and stirred for 5 min at RT. Aniline E (50 mg) was dissolved in pyridine (1 mL) and added to the solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ CH₃CN) to afford intermediate G (31 mg, 44%).

¹H-NMR (DMSO, 300 MHz): δ 8.90 (s, 1 H), 8.44 (d, J = 3.3 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H)₁ 7.65 (d, J = 8.7 Hz₁ 1 H), 7.41 (t, J = 8.1 Hz, 1 H), 7.27 (s, 1 H), 7.12 (d, J = 7.5 Hz₁ 2H), 7.06-7.01 (m, 2H), 6.80 (s, 1 H), 6.67 (d, J - 7.5 Hz, 1 H)₁ 5.20 (s, 1 H), 4.81 (d, J = 8.1 Hz, 1 H), 3.24-3.11 (m, 3H), 2.92 (d, J = 12.3 Hz, 1 H), 2.82 (s, 1 H)₁ 0.89-0.82 (m, 2H), 0.65 (m, 2H). LCMS m/z [M+H]⁺ C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.56 HPLC Tr (min), purity %: 3.37, 98%

Intermediate H

H

To a 50 mL flask containing 20 mL of DMF was added 1 mL of oxaiyl chloride slowly and stirred for 10 min at RT. 2-Bromo-ϊsonicotinic acid (100mg) was added to 2 mL of the above solution and stirred for 5 min at RT. Aniline E (50 mg) was dissolved in pyridine (1 mL) and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ CH₃CN) to afford intermediate H (32mg, 43%).

¹H-NMR (DMSO, 300 MHz): δ 8.91 (s, 1 H)₅ 8.43 (d, J = 3.3 Hz, 1 H)₁ 7.74 (d, J = 7.5 Hz, 1 H), 7.64(d, J = 8.5 Hz, 1 H), 7.45 (d, J = 8.1 Hz₁ 1 H), 7.23 (s, 1 H)₅ 7.15 (d, J = 7.5 Hz, 2H), 7.12-7.04 (m, 2H), 6.68 (s, 1 H), 6.54 (d, J = 7.5 Hz, 1 H)₁ 5.22 (s, 1 H), 4.76 (d, J = 8.1 Hz, 1 H), 3.34-3.15 (m, 3H), 2.97-2.91 (m Hz, 1 H), 2.81 (s, 1 H), 0.91 - 0.84 (m, 2H)₁ 0.65 (m, 2H).

LCMS m/z [M+H]⁺ C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.45 HPLC Tr (min), purity %: 3.33, 98%

Intermediate J

B1

I. SOCI₂, EtOH, 7O⁰C; II. EtOH₁ Pd/C, H₂ Mixed B1 (648mg, 2mmol) with EtOH (40 mL). Thionyl chloride (1.5 mL, 20mmol) was added dropwise over 10-15mins. The reaction mixture was then stirred at 7O⁰C for 16hrs. The mixture was concentrated under reduced pressure to give a solid which was then suspended in hexanes and stirred for 30mins. The solid was collected by filtration, washed with hexanes, and dried under high vacuum. The solid was dissolved in EtOH (50 mL). 5% Pd/C was added and the mixture stirred under 1 atm of H₂ for 3hrs. The mixture was filtered through Celite and concentrated under reduced pressure to give a solid. The solid was dried under high vacuum to give J

(632mg, 99%).

¹H NMR (300MHz₁ CD₃OD): δ 7.80 (m, 2H), 7.59 (m, 3H)₁ 4.39 (q, J = 6.9 Hz, 2H), 3.95 (t, J = 7.2 Hz, 2H)₁ 3.09 (t, J = 6.9 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H).

LC/MS (m/e): 274.1 [M +H]⁺ lntermedate K

J K

I. p-nitrobenzoyl chloride, DIPEA, DIVIAP, DMF, 50⁰C; II, Zn, HOAc/ACN intermediate J (632mg, 2mmol) was dissolved in anhydrous DMF (20 rnL). p- nitrobenzoyi chloride (197mg, 2.68mmol) was added followed by DIPEA (93OuL, 5.34mmol). DMAP (44mg, 0.35mmol) was added and the reaction stirred at 5O⁰C for 4hrs. Diluted reaction with EtOAc and washed with saturated aqueous sodium bicarbonate solution (2x), 5% aqueous citric acid solution and saturated sodium chloride solution. Dried organic extract over anhydrous sodium sulfate and concentrated under reduced pressure to give solid. Dissolved solid in acetonitrile and acetic acid. Added zinc powder and stirred for 6hrs. Filtered off solid and washed with acetonitrile. Concentrated under reduced pressure. Dissolved in EtOAc and washed with saturated aqueous sodium bicarbonate solution (2x) and saturated sodium chloride solution. Dried organic extract over anhydrous sodium sulfate and concentrated under reduced pressure. Purified with Combiflash (0-70% EtOAc in hexanes) to give K (740mg, 94%). ¹H NMR (300MHz₅ CDCi₃): δ 7.79 (d, J = 7.8Hz, 1 H), 7.67 (s, 1 H), 7.20 (m, 1 H), 7.04 (m, 1 H)₅ 6.99 (d, J - 8.7Hz, 2H), 6.79 (d, J = 7.8Hz, 1 H), 6.41 (d, J = 8.7Hz, 2H), 5.11 (bs, 1 H), 4.39 (q, J = 6.9 Hz, 2H), 3.41-3.11 (m, 3H)₁ 1.41 (t, J = 7.2 Hz, 3H) LC/MS (m/e): 393.1 [M+H]⁺ intermediate L

1. K₂CO₃, isobutyl chloroformate, THF; H. K

Dissolved 2-bromo nicotinic acid (360mg, 1.78mmoi) in anhydrous THF. Added potassium carbonate (738mg, 5.34mmoi) and then isobutyl chioroformate (233uL, 1.78mmol). Stirred for 60mins. Added intermediate K (698mg_; 1.78mmo!) and stirred for 72hrs. Diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution (2x) and saturated sodium chloride solution. Dried organic extract over anhydrous sodium sulfate and concentrated under reduced pressure. Purified with Combiflash (20-70% EtOAc in hexanes) to give L (465mg, 45%).

¹H NMR (300MHz, CDCI₃): δ 8.48(m, 1 H)₁ 7.98 (m, 2H), 7.80 (d, J = 7.8 Hz₁ 1 H)₁ 7.69 (S, 1 H), 7.39 (m, 3H), 7.18 (m, 4H), 7.06 (m, 1 H), 6.78 (d, J = 7.8 Hz, 1 H), 5.08 (m, 1 H), 5.11 (bs, 1 H)₅ 4.40 (q, J = 7.2 Hz, 2H), 3.49 (m, 1 H), 3.14 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H)

LC/MS (m/e): 576.0 and 578.0 [M+Hf

Intermediate M

I. pyrrolidine

Dissolved L (460mg, O.δmmol) in pyrrolidine and stirred for 16hrs at room temperature. Concentrated under reduced pressure and purified with Combiflash (20-100% EtOAc in hexanes) to give M (214mg, 47%).

¹H NMR (300MHz, CDCi₃): δ 8.46 (s, 1 H), 8.28 (d, J = 5.1 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 1 H), 7.80 (d, J = 7.8 Hz, 1 H), 7.69 (s, 1 H)₁ 7.43 (m, 2H)₁ 7.16 (m, 4H), 7.04 (m, 1 H), 6.79 (m, 2H), 5.12 (m, 1 H), 4.40 (q, J = 7.2 Hz, 2H), 3.41 (m, 5H), 3.14 (m, 2H), 1.90 (m, 4H), 1.41 (t, J = 7.2 Hz, 3H)

LC/SviS (m/e): 567.1 [Jvl+Hf Intermediate N

I. NaOH(aq), ACN/MeOH

Mixed M (194mg, 0.34mmol) in MeOH and acetonitrile. Dissolved NaOH (42mg, 1.1 mmol) in water and added to the reaction mixture in one portion. Stirred for 6hrs. Neutralized reaction to pH of 9 with HCI(aq) and then concentrated under reduced pressure to give yellow solid of N (quantitative) which was used without further process. ¹H NMR (300MHz, DMSOd₆): δ 7.82 (m, 1 H), 7.70 (d, J = 7.8Hz, 1 H), 7.29 (d, J = 7.2 Hz, 1 H)₅ 7.18 (m, 1 H), 7.07 (m, 4H), 6.75 (m, 3H), 6.36 (m, 1 H)₁ 3.41 (m, 4H), 3.04 (m, 3H), 1.72 (m, 4H). LC/MS (m/e): 539.1 [M+Hf Intermediate P

To a solution of the amine C (0.3 g, 0.1 mM) in dry pyridine (1.5 mL) was added slowly a solution of 2-Fluoro-4-nitrobenzoyi chloride (0.2 g, 0.1 mM) in CH₃CN (1 mL) and stirred under N₂ at RT fro 2 h. Volatiles were removed under reduced pressure at 4O⁰C, the resulting residue dissolved in EtOAc (50 mL) and the organic phase was washed 2x each with aqueous dilute NaHCO₃, then H₂O followed by brine, Voiatiles were removed under reduced pressure at 40⁰C. The resulting residue was purified by silica gel column using 50% EtOAc in hexanes with a gradient from 50% to 100% to afford the corresponding nitro intermediate (0.31 g, 64. The nitro compound was hydrogenated using Pd on C (10%, 0.2g) in 150 mL Ethanol and 1 mL 1 N HCI under an atmosphere of H₂ (balloon). Volatiles were removed under reduced pressure at 4O⁰C to afford P (0.31g, 99%).

LC/MS (m/e): 522.03 [M+H]⁺ Intermediate Q

B1

Preparation of intermediate Q was performed as shown for intermediate D followed by a reduction of the nitro precursor (0.51 g) with iron powder (1.1 g) in HOAc (50 ml_) at 70 ⁰C with vigorous stirring for 5 min. Volatiies were removed under reduced pressure at 40⁰C, the resulting residue dissolved in EtOAc (150 mL) and the organic phase was washed 2x each with aqueous dilute NaHCOs, then H₂O followed by brine. Volatiies were removed under reduced pressure at 4O⁰C, the resulting residue was purified by silica gel column using 50% EtOAc in hexanes with a gradient from 50% to 100% to afford intermediate Q (0.41 g, 85%).

¹H-NMR (DMSO, 300 MHz): δ 8.55 (d, J = 3.6 Hz₇ 1 H), 7.84 (d, J = 2.1 Hz₁ 1 H), 7.64 (s, 1 H), 7.27 (d, J = 8.7 Hz₁ 1 H), 6.73-6.70 (m, 3H), 6.28 (d, J = 8,7 Hz, 2H), 5.52 (s, 1 H), 3.10 (m, 2H), 2.49 (m, 2H), 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+Hf C₂₃Hi₈BrN₃O₄S requires: 512.38. Found 513.89

HPLC Tr (min), purity %: 2.53, 90%

Intermediate R

To a 50 ml fiask containing 20 ml_ of DMF added 1 mL of oxalyl chloride slowly, an orange solution formed after the addition. 100mg of 3-Bromo-4-Pyridinecarboxylic Acid was dissolved in 2 mL of the above orange solution and stirred for 5mins at room temperature. Then 50mg of the intermediate E was dissolved in 1 mL pyridine and then this pyridine solution was added to the above orange carboxylic acid soiution. Reaction was finished in 5mins at room temperature and was quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was dissolved in CH₃CN and water and purified with prep HPLC to afford intermediate R (27mg, 40%).

¹H-NMR (DMSO, 300 MHz): δ 8.95 (S, 1 H), 8.43 (d, J = 3.3 Hz₁ 1 H), 7.76 (t, J - 7.5 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.40 (d, J - 8.1 Hz, 1 H), 7.25 (s, 2H), 7.15 (t, J = 7.8 Hz, 1 H), 7.07-7.02 (m, 2H), 6.82 (s, 1 H), 6.67 (d, J = 7.2 Hz, 1 H)₅ 5.22 (s, 1 H), 4.88 (d, J = 8.7 Hz, 1 H), 3.28-3.12 (m, 3H), 2.95 (d, J = 12.3 Hz, 1 H), 2.82 (s, 1 H), 0.84-0.80 (m, 2H), 0.66 (me, 2H).

LCMS m/z [M+H]⁺ C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.02 HPLC Tr (min), purity %: 3.30, 98% Intermediate S

To a 10 mL flask containing 2 ml of NMP was added 100mg of 3-Fluoro-4-Nitro, to the above solution was added 0.1 mL of Thionyl Chloride and stirred for 10 min at RT. Then 77 mg of intermediate C was dissolved in 1 mL NMP and added to the above solution followed by addition of 0.7mL of Triethylamine. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was used directly in the next step. The nitro intermediate was dissolved in ethanol (5 mL), 0.1 mL of 1 N HCI solution and 100mg Pd-C (10%) catalyst were added and the reaction mixture was stirred under H₂ balloon overnight at RT. After flushing with N₂, the catalyst was filtered over celite and the filtrate was evaporated and purified with prep HPLC to afford intermediate S <100mg, 88%) as an off-white powder. ¹H-NMR (DMSO, 300 MHz): .5 8.51 (d, J = 4.2 Hz, 1 H), 7.76 (d, J - 6.9 Hz, 1 H), 7.63 (s, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.11 (t, J - 7.5 Hz, 1 H), 6.83 (d, J = 8,4 Hz, 1 H)₁ 6.64 (d, J = 12.3 Hz, 1 H), 6.51-6.40 (m, 2H), 4.87 (s, 1 H), 3.09 (me, 3H), 2.79 (me, 1 H), 0.70-0.69 (m, 2H), 0.56-0.55 (m, 2H). LCMS m/z [M+H]⁺ C₂₃H₂₀FN₃O₂S requires: 421.49. Found 421.28 HPLC Tr (min), purity %: 3.08, 98%

Intermediate T

To a 20 mL fiask containing 20 mL of DMF was added 1 mL of oxalyi chloride slowly. An orange solution formed after the addition. 100mg of 2-Bromo-3-Pyridinecarboxyiic

Acid was dissolved in 2 mL of the above orange solution and stirred for 5mins at room temperature. Then 50mg of the intermediate S was dissolved in 1 mL pyridine and this pyridine solution was added to the above orange carboxylic acid solution.

Reaction was finished in 5mins at room temperature and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was dissolved in CH₃CN and water and purified with prep HPLC to afford intermediate T

(53mg, 74%).

¹H-NMR (DMSO, 300 MHz): δ 10.56 (s, 1 H), 8.54 (d, J = 4.2 Hz, 1 H), 8.46 (d, J = 4.8 Hz₁ 1 H), 7.94 (d, J - 6.3 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 2H), 7.66 (s, 1 H)₇ 7.53 (dd, J = 4.8, 7.2 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 1 H), 7.14 (t, J = 4.2 Hz, 1 H), 6.95-6.90 (m, 2H), 6.78 (d, J = 7.5 Hz, 1 H)₁ 4.88 (d, J = 8.7 Hz, 1 H), 3.25-3.05 (m, 3H), 2.81-2.80 (m, 1 H), 0.70 (m, 2H), 0.56 (m, 2H) LCMS m/z [M-J-H]⁺ C₂₉H₂₂BrFN₄O₃S requires: 605.48. Found 605.52 HPLC Tr (min), purity %: 3.15, 98%

Intermediate U

To a 20 ml flask containing 20 mL of DMF added 1 mL of oxalyi chloride slowly, an orange solution formed after the addition. 300mg of 3-Ch!oro-6-methyl-pyridazine-4- carboxylic acid was dissolved in 4mL of the above orange solution and stirred for 5mins at room temperature. Then 150mg of the intermediate E was dissolved in 2 mL pyridine and then this pyridine solution was added to the above orange carboxylic acid solution. Reaction was finished in 5mins at room temperature and was quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was dissolved in CH₃CN and water and purified with prep HPLC to afford intermediate U (HOmg, 53%).

¹H-NMR (DMSO, 300 MHz): δ 8.35 (d, J = 4.2 Hz, 1 H), 7.94 {s, 1 H), 7.66 (s, 1 H), 7.53 (d, J = 7.2 Hz, 2H)₁ 7.19 (t, J = 7.8 Hz, 1 H), 6.98-6.80 (m, 3H), 6.75 (d, J = 7.5 Hz, 1 H), 4.18 (me, 1 H), 3.28-3.05 (m, 3H), 2.35-2.30 (m, 1 H), 1.82 (s, 3H), 0.73 (m, 2H), 0.55 (m, 2H)

LCMS m/z [M+Hf C₂₉H₂₄CIN₅O₃S requires: 558.05. Found 558.21 HPLC Tr (min), purity %: 3.18, 98% Intermediate V

To a 20 mL flask containing 20 ml_ of DMF added 1 mL of oxaly! chloride slowly, an orange solution formed after the addition. 60 mg of 4-bromopiconilic acid was dissolved in 2 mL of the above orange solution and stirred for 5mins at room temperature. Then 30 mg of the intermediate E was dissolved in 1 mL pyridine and then this pyridine solution was added to the above orange carboxyiic acid solution. Reaction was finished in 5mins at room temperature and was quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was dissolved in CH₃CN and water and purified with prep HPLC to afford intermediate V (25mg, 58%).

¹H-NMR (DMSO, 300 MHz): δ 8.75 (s, 1 H), 8.32 (s, 1 H), 7.65 (d, J = 7.2 Hz₁ 1 H), 7.40 (S₁ 1 H), 7.38 (d, J = 7.5 Hz, 2H)₁ 7.36 (s, 1 H), 7.18 (t, J = 7.8 Hz, 1 H), 7.08-7.02 (m, 2H), 6.84 (s, 1 H), 6.75 (d, J = 7.2 Hz, 1 H), 5.20 (s, 1 H), 4.92 (s, 1 H), 3.30-3.08 (m, 3H), 2.96 (s, 1 H), 2.82 (s, 1 H), 0.85-0.83 (m, 2H), 0.65 (me, 2H).

LCMS m/z [M+Hf C₂₉H₂₃BrN₄O₃S requires; 587.07. Found 587.28 HPLC Tr (min), purity %: 3.30, 98%

Example 1

To a solution of intermediate E (80 mg, 0.2 mM) in dry pyridine (2 ml) was added 2- bromonicotinic acid (60 mg, 0.3 mM) and HATU (114 mg, 0.3 mM) and the solution stirred under N₂ at RT for 2 h. Volatiies were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (20% CH₃CN in H₂O with a gradient from 20% to 95%) to afford example 1 (63 mg, 54%) as a white powder after lyophilization.

¹H-NMR (DMSO, 300 MHz): δ 8.82 (s, 1 H), 8.41 (d, J = 3.3 Hz, 1 H), 7.89 (d, J - 7.5 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 2H), 7.34 (s, 1 H)₁ 7.21 (t, J = 7.8 Hz, 1 H), 7.04-7.01 (m, 2H), 6.84 (s, 1 H), 6.73 (d, J = 7.5 Hz, 1 H), 5.27 (s, 1 H), 4.96 (d, J = 11.7 Hz, 1 H), 3.32-3.16 (m, 3H), 2.97 (d, J = 16.2 Hz, 1 H), 2.83 (s, 1 H), 0.85-0.83 (m, 2H)₁ 0.66 (me, 2H).

LCMS m/z [M+Hf C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.23 HPLC Tr (min), purity %: 3.31 , 95% Example 2

To a solution of the amine E (0.05Og, 0.12 mM) in dry pyridine (1 ml_) was added slowly a solution of 2-iodobenzoy! chloride (0.065 g, 0.27 mM) in CH₃CN (1 mL) and stirred under N₂ at RT fro 2 h. Volatiies were removed under reduced pressure at 4O⁰C, the resulting residue dissolved in EtOAc (150 mL) and the organic phase was washed 2x each with aqueous dilute NaHCO₃, then H₂O followed by brine. The residue was purified by prep HPLC (0% to 95% water/ CH₃CN) to afford 2 (3.2 mg, 5%). ¹H-NMR (DMSO, 300 MHz): δ 10.44 (s, 1 H)₁ 8.48 (d, J = 4.2 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.71 (d, J = 6.9 Hz, 1 H), 7.60 (s, 1 H), 7.46-7.39 (m, 3H), 7.22 (m, 2H), 7.05 (m, 1 H), 7.94 (d, J = 6.3 Hz, 2H), 7.81 (m, 1 H), 3.16-3.05 (m, 2H)₁ 2.76 (m, 2H), 0.66 (m, 2H), 0.51 (m, 2H). LCMS m/z [M+H]⁺ C₃₀H₂₄IN₃O₃S requires: 633.50. Found 633.93. HPLC Tr (min), purity %: 2.45, 90%.

Example 3

An oven-dried Schlenk tube equipped with a teflon valve was charged with a magnetic stir bar, Cu! (0.6 mg, 0.003 mmol, 5 mo! %), Cs₂CO₃ (39 rng, 0.12 mmol). The tube was evacuated and backfilled with argon (this procedure was repeated three times). Under a counter flow of argon, pyrolidine and the aryl iodide 2 and DMF (2 ml_) were added. Finally, 2-acetylcyciohexanone (1.8 mg, 0.013 mmol, 20 mol%) was added via syringe, the tube was sealed and the mixture was allowed to stir under argon at 70 ⁰C overnight. Upon completion of the reaction, the mixture was diluted with ethyl acetate, passed through a fritted glass filter to remove the inorganic salts and the solvent was removed with the aid of a rotary evaporator. The residue was purified by prep HPLC (0% to 95% water/ CH₃CN) to afford 3 (14mg, 28%).

¹H-NMR (DMSO, 300 MHz): 610.41 (s, 1 H)₇ 8.54 (d, J = 2.7 Hz, 1 H), 7.77 (d, J - 8.1 Hz, 1 H), 7.65 (s, 1 H), 7.50 (d, J = 7.8 Hz, 2H), 7.25-7.23 <m, 3H), 7.10 (t, J = 7.5 Hz, 1 H), 6.96 (d, J = 6.9 Hz, 2H), 6.84 (d, J = 6.9 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 1 H), 6.69 (t, J = 7.2 Hz, 1 H), 4.89 (s, 1 H), 3.25-3.05 (m, 7H), 2.81-2.80 (m, 1 H), 1.81 (S, 4H), 0.70 (m, 2H), 0.56 (m, 2H). LCMS m/z [M+Hf C₃₄H₃₂N₄O₃S requires: 577.70. Found 577.15. HPLC Tr (min), purity %: 3.63, 98%.

Example 4

To a 50 mL flask containing 20 mL of DMF was added 1 mL of oxalyl chloride slowly and stirred for 10 min at RT. 100 mg of 3-bromo-isonicottnic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of intermediate E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 4 (27mg, 40%).

¹H-NMR (DMSO, 300 MHz): 6 8.95 (s, 1 H), 8.43 (d, J - 3.3 Hz, 1 H)₁ 7.76 (t, J = 7.5 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 1 H), 7.25 (s, 2H), 7.15 (t, J = 7.8 Hz, 1 H), 7.07-7.02 (m, 2H), 6.82 (s, 1 H), 6.67 (d, J = 7.2 Hz, 1 H), 5.22 (s, 1 H), 4.88 (d, J = 8.7 Hz, 1 H), 3.28-3.12 (m, 3H), 2.95 (d, J = 12.3 Hz, 1 H), 2.82 (s, 1 H), 0.84-0.80 (m, 2H), 0.66 (me, 2H).

LCMS m/z [MH-H]⁺ C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.02 HPLC Tr (min), purity %: 3.30, 98% Example 5

To a 50 mL fiask containing 20 mL of DMF was added 1 mL of oxalyi chloride siowly and stirred for 10 min at RT. 100 mg of 3-bromo-pyridine-2-carboxyiic acid was dissolved in 2 mL of the solution and stirred for 5 min at RT. A solution of E (50 mg) dissolved in pyridine (1 mL) and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC {0% to 95% water/ Acetonitrile) to afford 5 (29mg, 42%).

¹H-NMR (DMSO, 300 MHz): δ 8.92 (s, 1 H), 8.45 (d, J = 3.3 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 7.28 (s, 1 H), 7.13 (d, J = 7.8 Hz, 2H), 7.09-7.04 (m, 2H), 6.81 (s, 1 H), 6.64 (d, J = 7.5 Hz, 1 H), 5.21 (s, 1 H), 4.85 (d, J = 8.5 Hz, 1 H), 3.23-3.16 (m, 3H), 2.94 (d, J = 12.3 Hz, 1 H), 2.80 (s, 1 H), 0.86-0.81 (m, 2H), 0.66 (s, 2H).

LCMS /n/z fM+Hf C₂₉H₂₃BrN₄O₃S requires: 587.07. Found 587.34

HPLC Tr (min), purity %: 3.31 , 98%

Example 6

Compound 1 (16 mg, 0.03 mM) and 2-methylpyrroiidine (0.1 mL) were dissolved in DMF (1 mL) and stirred at 70⁰C overnight. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrile) to afford 6 (15 mg, 94%) as a white powder.

¹H-NMR (DMSO₁ 300 MHz): ,δ 10.53 (s, 1 H)₁ 8.50 (d, J = 3.9 Hz, 1 H)₁ 8.08 (d, J = 4.5 Hz, 1 H), 7.73 (t, J = 7.8 Hz₁ 2H), 7.61 (s, 1 H), 7.43 (d, J = 8.1 Hz, 2H), 7.22 (t, J = 7.8Hz, 1 H), 7.05 (t J = 7.5Hz, 1 H), 6.94 (d, J = 7.8 Hz, 2H)₁ 6.71 (t, J = 7.5 Hz, 1 H)₁ 4.82 (me, 1 H), 4.21 (dd, J = 6.0, 12.3 Hz, 1 H)₁ 3.66-3.37 (m, 2H), 3.16-3.00 (m, 3H), 2.76-2.44 (m, 1 H), 2.01-1.87 (m, 1 H), 1.85-1.72 (m, 1 H), 1.70-1.67 (m, 1 H), 1.56- 1.48 (m, 1 H), 1.11 (d, J = 5.7 Hz, 1 H), 0.65 (m, 2H), 0.51 (m, 2H). LCMS m/z [M+H]⁺ C₃₄H₃₃N₅O₃S requires: 591.72. Found 591.68 HPLC Tr (min), purity %: 3.25, 98%

Example 7

Compound 1 (14 mg, 0.02 mM) and 3,3-difluoroazetidine (20 mg) were dissolved in DMF (1 mL) and triethylamine (0.5 mL). The reaction mixture was stirred at 7O⁰C overnight. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrile) to afford 7 (6 mg, 42%) as a white powder.

¹H-NMR (DMSO, 300 MHz): δ 10.47 (s, 1 H), 8.54 (d, J = 3.3 Hz, 1 H), 8.26 (d, J = 3.3 Hz, 1 H), 7.77 (d, J = 7.8 Hz₁ 2H), 7.66 (s, 1 H), 7.47 (d, J ~ 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.98 (d, J = 8.1 Hz, 2H), 6.88-6.85 (m, 2H), 4.92 (me, 1 H), 4.32-4.20 (m, 4H), 3.19-3.11 (m, 3H), 2.80 (s, 1 H), 0.70 (m, 2H), 0.57 (s, 2H). LCMS m/z [M-I-H]⁺ C₃₂H₂₇F₂N₅O₃S requires: 600.65. Found 600.48 HPLC Tr (min), purity %: 3.18, 98%

Example 8

Compound 2 (23 mg, 0.036 mM) and 4-fiuoroρhenylboronic acid (10 mg) were dissolved in DME (2 mL) and water (1 ml_). To the above solution was added Palladium tetrakis (triphenylphosphine) (6 mg) and potassium carbonate (20 mg). The reaction mixture was heated to 120⁰C for 10 mtn in a microwave reactor. The reaction mixture was filtered and volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrile) to afford 8 (8 mg, 36%).

¹H-NMR (DIVISO₁ 300 MHz): δ 8.57 (s, 1 H), 8.31 (dd, J = 1.2, 7.8 Hz, 1 H), 8.17-7.90 (m, 7H), 7.79-7.74 (m, 3H), 7.77-7.49 (m, 5H), 7.32 (d, J = 7.2 Hz, 1 H), 5.46 (s, 1 H), 3.85-3.61 (m, 4H), 3.36-3.30 (m, 1 H), ), 0.69 (m, 2H), 0.55 (m, 2H). LCMS m/z [M+H]⁺ C₃₄H₂₇N₃O₃S₂ requires: 602.70. Found 602.02.

HPLC Tr (min), purity %: 3.37, 98%.

Example 9

Compound 1 (14 mg, 0.02 mM) and 3,3-difluoropyrrolidine (20 mg) were dissolved in DMF (1 rnL) and triethylamine (0.5 ml_). The reaction mixture was heated to 14O⁰C for 8 h in a microwave reactor. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitriie) to afford 9 (8 mg, 44%).

¹H-NMR (DMSO, 300 MHz): δ 10.55 (s, 1 H), 8.53 (d, J = 4.2 Hz₁ 1 H), 8.22 (d, J = 4.8 Hz, 1 H), 7.77 (d, J = 7.8 Hz₁ 2H)₅ 7.70 (d, J = 7.8 Hz, 1 H), 7.65 (s, 1 H), 7.49 (d, J = 8.1 Hz, 1 H)₇ 7.24 (t, J = 7.2 Hz, 1 H), 7.09 (t, J = 6.9 Hz, 1 H)₁ 6.98 (d, J = 8.4 Hz, 1 H), 6.86-6.77 (m, 3H), 4.87 (me, 1 H)₁ 3.77-3.59 (m, 6H), 3.15-3.09 (m, 3H), 2.82-2.80 (m, 1 H), 0.69 (m, 2H), 0.55 (m, 2H). LCMS m/z [M÷H]⁺ C₃₃H₂₉F₂N₅O₃S requires: 613.68. Found 614.03 HPLC Tr (min), purity %: 2.61 , 98%

Example 10

Compound 1 (15 mg, 0.02 mM) and spirocyciicamine (25 mg) [Angew Chem inti edition English 2008, 47, p4512] were dissolved in DMF (1 mL) and triethylamine (0.5 mL). The reaction mixture was stirred at 7O⁰C for 16 h. Voiatiles were removed under reduced pressure at 40⁰C and the resulting residue was purified by preparative HPLC using a gradient 0% to 95% water/ Acetonitrϋe to afford 10 (5 mg, 35%) as a white powder.

¹H-NMR (DMSO, 300 MHz): δ 10.52 (s, 1 H), 8.49 (d, J = 3.3 Hz₁ 1 H), 8.11 (d, J = 3.3 Hz, 1 H), 8.08 (d, J = 5.7 Hz, 1 H), 7.75-7.65 (m, 2H), 7.61 (s, 1 H)₁ 7.44 (d, J = 7.5 Hz, 2H), 7.22 (t, J = 7.8 Hz, 1 H), 7.05 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 8.1 Hz, 1 H), 6.81- 6.71 (m, 2H), 4.82 (me, 1 H)₁ 3.69 (s, 3H), 3.39 (s, 2H), 3.16-3.05 (m, 4H), 2.88 (s, 2H), 2.75 (s, 1 H), 0.65 (d, J = 6.6 Hz, 2H), 0.50 (s, 2H).

LCMS m/z [M+H]⁺ C₃₄H₃₁N₅O₄S requires: 606.71. Found 606.48 HPLC Tr (min), purity %: 3.15, 98% Example 11

To a 50 ml_ flask containing 20 ml_ of DMF was added 1 mL of oxalyl chloride slowly and stirred for 10 min at RT. 100 mg of the 2-thiophen-2-yl-benzoic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of intermediate E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford the product 11 (27 mg, 40%). ¹H-NMR (DMSO, 300 MHz):δ 8.51 (s, 1 H), 7.78 (d, J - 7.8 Hz, 1 H), 7.55-7.51 (m, 3H), 7.40-7.26 (m, 3H), 7.26-7.22 (m, 3H), 7.02-6.97 (m, 5H), 6.79 (d, J = 7.8 Hz₁I H), 4.98-4.90 (m, 1 H), 3.26-3.07 (m, 4H)₁ 2.81-2.76 (m, 1 H)₁ 0.76-0.62 (m, 2H), 0.60-0.56 (m, 2H). LCMS m/z [M+H]⁺ C₃₄H₂₇N₃O₃S₂ requires: 590.70. Found 590.97.

HPLC Tr (min), purity %: 3.20, 98%. Example 12

Compound 4 (15 mg, 0.02 mM) was dissolved in azetidine (0.5 mL) and the reaction mixture was stirred at 70⁰C for 16h. Voiatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrϋe) to afford 12 (10 mg, 71%).

¹H-NMR (DMSO, 300 MHz): δ 10.69 (s, 1H), 8.54 (s, 1H), 8.05 (d, J = 5.4 Hz, 1H), 7.98(s, 1H), 7.77 (d, J =8.1 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.26 (t, J = 8.1 Hz, 1H)₁7.09-6.83 (m, 3H), 4.87 (me, 1H), 3.91 (t, J = 6.9 Hz, 3H), 3.21-3.05 (m, 4H), 2.81 (s, 1H), 2.28 (t,J=7.2 Hz, 2H), 0.70 (d, J= 6.6 Hz, 2H), 0.55 (s, 2H).

LCMS m/z [M+H|⁺ C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.28 HPLC Tr (min), purity %: 2.60, 98% Example 13

To a 50 ml_ flask containing 20 ml of DMF was added 1 mL of oxalyl chioride siowiy and stirred for 10 min at RT. 100mg of 2-isopropyi-benzoic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitriie) to afford 13 (127 mg, 62%).

¹H-NMR (DMSO, 300 MHz): δ 8.59 (s, 1 H)₇ 7.80 (d, J = 7.5 Hz, 1 H), 7.46-7.33 (m, 6H), 7.26-7.06 (m, 2H), 7.06-7.04 (m, 4H), 6.82 (d, J = 6.3 Hz, 1 H), 4.94 (s, 1 H), 3.29-3.08 (m, 1 H)₁ 3.08-2.77 (m, 4H), 1.19 (d, J = 6.6 Hz, 1 H)₁ 0.74-0.70 (m, 2H), 0.62-0.57 (m, 2H).

LCMS m/z [M+Hf C₃₃H₃₁N₃O₃S requires: 550.75. Found 550.08. HPLC Tr (min), purity %: 3.40, 98%. Example 14

To a 50 mL fiask containing 20 ml_ of DMF was added 1 mt_ of oxalyl chioride slowly and stirred for 10 min at RT. 100mg of the 4-trifluoromethyl nicotinic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 14 (56mg, 82%).

¹H-NMR (DMSO, 300 MHz): δ 10.83 (s, 1 H), 8.95-8.97 (m, 1 H)₁ 8.54 (d, J = 3.9 Hz, 1 H), 7.88 (d, J = 5.1 Hz₁ 1 H), 7.77 (d, J - 7.5 Hz, 1 H), 7.47 (d, J - 8.4 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1 H), 7.11 (t, J = 6,6 Hz, 1 H), 7.01 (d, J - 8.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1 H), 4.88 (s, 1 H), 3.05-3.22 (m, 4H)₁ 2.80-2.81 (m, 1 H), 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+H]⁺ C₃₀H₂₃F₃N₄O₃S requires: 577.60. Found 577.11.

HPLC Tr (min), purity %: 3.16, 98%. Example 15

To a 50 mL flask containing 20 mL of DMF was added 1 mL of oxaiyl chloride siowly and stirred for 10 min at RT. 100mg of 4-methoxy benzoic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 15 (26mg, 48%).

¹ H-NMR (DMSO₁ 300 MHz): δ 10.03 (s, 1 H), 8.45 (d, J = 4.2 Hz, 1 H), 7.84 (d, J = 8.4 Hz₁ 2H), 7.71 (d, J = 7.8 Hz, 1 H), 7.53 (s, 1 H), 7.50 (d, J = 8.4 Hz, 2H), 7.18 (t, J = 6.9 Hz, 1 H), 7.03-6.92 (m, 4H), 6,78 (d, J - 6.9 Hz₁ 1 H), 4.84 (me, 2H)₇ 3.16-2.78 (m, 3H), 2.77-2.75 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+Hf C_3IH₂₇N₃O₄S requires: 538.63. Found 538.01

HPLC Tr (rnin), purity %: 3.19, 98% Example 16

Intermediate C (80mg) and intermediate F (20mg) were dissolved in DMF (3m L), and PyBroP (65mg) and DMAP (17mg) were added to the above soiution. The reaction mixture was heated at 8O⁰C for 1 hour. The solvent was evaporated and the residue was purified with preparative HPLC (0% to 95% water/ Acetonitrile) to afford 16 (30mg, 20%).

¹H-NMR (DMSO, 300 MHz): δ 10.39 (s, 1 H)₁ 8.55 (d, J = 3.9 Hz, 1 H), 7.82 (d, J = 7,2 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.60-7.46 (m, 3H)₅ 7.32 (d, J = 7.2 Hz, 1 H), 7.12 (t, J = 7.5 Hz, 1 H)₁ 7.06 (t, J = 7.5 Hz₁ 1 H)₁ 6.85 (d, J = 7.5 Hz, 1 H), 4.76 (me, 1 H), 3.38-3.10 (m, 3H), 2.82-2.75 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+H]⁺ C₃₀H₂₂F₄N₄O₃S requires: 595.58. Found 595.20 HPLC Tr (min), purity %: 3.30, 98% Example 17

2-Benzylbenzoic acid (100 mg) was dissolved in NMP (3 mL) and thionyl chloride (0.41 rnL) was added. After stirring for 5 min, intermediate E (50mg) was added to the above solution. The reaction was completed after stirring for 10 min at RT. The reaction mixture was quenched with water and extracted with EtOAc. The solvent was evaporated and the residue was purified with preparative HPLC (0% to 95% water/ Acetonitrile) to afford 17 (30 mg, 45%).

¹H-NMR (DMSO, 300 MHz): δ 10.36 (s, 1 H), 8.50 (d, J = 3.9 Hz, 1 H), 7.72 (d, J - 7.8 Hz, 1 H), 7.61 (s, 1 H), 7.45 (d, J - 8.4 Hz, 1 H), 7.37-7.34 (m, 2H), 7.32-7.11 (m, 3H), 7.10-7.03 (m, 5H)₁ 6.92 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 6.9 Hz, 1 H)₇ 4.83 (me, 1 H), 4.01 (s, 2H), 3.22-3.00 (m, 3H), 2.78-2.73 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+H]⁺ C₃₇H₃₁N₃O₃S requires: 598.73. Found 598.12 HPLC Tr (min), purity %: 3.45, 98% Example 18

Intermediate V (10 mg, 0.013 imM) was dissolved in azetidine (0.5 mL) and the reaction mixture was stirred at 7O⁰C for 3 h. Volatiies were removed under reduced pressure at 40⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ MeCN) to afford 18 (5 mg, 45%). ¹H-NMR (DMSO, 300 MHz): δ 10.61 (s, 1 H), 8.55 (d, J - 3.6 Hz, 1 H), 8.14 (d, J = 5.1 Hz₁ 1 H), 7.72 (Ci₁ J = 7.8 Hz, 1 H), 7.73-7.62 (m, 3H), 7.24 (s, 1 H)₁ 7.01 (t, J = 8.7 Hz₅ 1 H)₅ 6.84 (s, 1 H)₁ 6.57-6.52 (m, 1 H), 4.87 (me, 1 H), 4.08-3.58 (m, 3H), 2.85-2.66 (m, 4H), 2.53 (s, 1 H)₁ 2.29-2.15 (m, 2H), 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+H]⁺ C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.45

HPLC Tr (min), purity %: 2.56, 98%

Example 19

Intermediate G (15 mg, 0.02 mM) was dissolved in azetidine (0.5 mL) and the reaction mixture was stirred at 7O⁰C for 16 h. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrϋe) to afford 19 (10 mg, 70%). ¹H-NMR (DMSO, 300 MHz): δ 10.55 (s, 1 H), 8.55 (d, J - 3.6 Hz, 1 H), 8.18 (d, J = 5.1 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.70-7.66 (m, 3H), 7.25 (t, J = 7.8 Hz, 1 H), 7.07 (t, J = 6.9 Hz, 1 H), 6.85-6.83 (m, 1 H), 6.49-6.47 (m, 1 H), 4.88 (me, 1 H), 4.01-3.38 (m, 3H), 2.95-2.56 (m, 4H), 2.49 (s, 1 H), 2.39-2.30 (m, 2H), 0.70 (m, 2H), 0.56 (m, 2H). LCMS m/z [M÷H]⁺ C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.39 HPLC Tr (min), purity %: 2.54, 98%

Example 20

To a 50 mL fiask containing 20 ml_ of DMF was added 1 ml_ of oxalyl chloride siowly and stirred for 10 min at RT. 100 mg of 1-Methyl-1H~indole-7-carboxylic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 20 (14 mg, 20%).

¹H-NMR (DMSO, 300 MHz): δ 10.66 (s, 1 H), 8.52 (d, J = 3.6 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.66 (S, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 7.35 (d, J = 3.0 Hz, 1 H), 7.28-7.22 (m, 2H)₁ 7.11-6.99 (m, 4H), 6.51 (d, J = 2.4 Hz, 1 H), 4.88 (me, 1 H), 3.68 (s, 3H), 3.25- 3.10 (m, 3H), 2.80-2.75 (m, 1 H), 0.70 (m, 2H), 0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₃₃H₂₈N₄O₃S requires: 561.67. Found 561.39 HPLC Tr (min), purity %: 2.58, 98% Example 21

Intermediate H (15 mg, 0.02 mM) was dissolved in azetidine (0.5 mL) and the reaction mixture was stirred at 7O⁰C overnight. VoSatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitriie) to afford 21 (13 mg, 73%).

¹H-NMR (DMSO, 300 MHz)IdIO-SO(S₁1H).8.54 (d, J = 3.9 Hz₁1H), 8.11 (d, J =5.7 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 7.52 (d, J= 8.7 Hz, 2H), 7.31-7.23 (m, 1H), 7.05-6.98 (m, 4H)₁6.83-6.80 (m, 1H), 4.86 (me, 1H), 4.13 (t, J = 7.8 Hz, 4H)₅ 3.21-3.05 (m, 3H), 2.81-2.80 (m, 1H), 2.42 (t, J = 7.2 Hz, 2H), 0.70 (m, 2H), 0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.21

HPLC Tr (min), purity %: 2.58, 98%

Example 22

To a 50 mL flask containing 20 m!_ of DMF was added 1 ml_ of oxalyl chloride slowly and stirred for 10 rniπ at RT. 100 mg of S-methyl-thiophene-^-carboxylic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitriie) to afford 22 (11 mg, 17%). ¹H-NMR (DIvISO, 300 MHz): δ 10.02 (s, 1 H), 8.54 (d, J - 4.2 Hz, 1 H)₅ 7.77 (d, J - 7.8 Hz, 1 H), 7.66 (S, 2H), 7.47 (d, J = 7.5 Hz₇ 2H), 7.26 (t, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 7.01 -6.98 (m, 2H), 6.85-9.82 (m, 1 H), 4.90 (me, 1 H), 3.21-3.11 (m, 3H), 2.83-2.80 (m, 1 H), 2.38 (s, 3H), 0.70 (m, 2H), 0.56 (m, 2H). LCMS m/z [M+H]⁺ C₂₉H₂₅N₃O₃S₂ requires: 528.66. Found 528.04 HPLC Tr (min), purity %: 3.23, 98%

Example 23

Intermediate E (20mg) and i-PhenyM H-Pyrazole-S-carboxylic acid chloride (18mg) was dissolved in Pyridine (2 mL) and the reaction mixture was stirred for 30 min. The reaction was quenched with water and extracted with EtOAc (20 mL). The solvent was evaporated and the residue was purified with preparative HPLC (0% to 95% water/ Acetonitrϋe) to afford 23 (24mg, 60%).

¹H-NMR (DMSO, 300 MHz): δ 10.59 (s, 1 H)₁ 8.53 (d, J = 4.2 Hz, 1 H), 7.79 (s, 1 H), 7.75 (d, J = 6.9 Hz, 1 H), 7.65 (s, 1 H), 7.42-7.36 (m, 6H), 7.25 (t, J = 7.5 Hz, 1 H), 7.08 (t, J = 7.5 Hz, 1 H)₁ 6.95 (d, J = 8.4 Hz, 2H)₁ 6.82 (d, J = 7.8 Hz₁ 1 H), 4.86 (me, 1 H), 3.20-3.04 (m, 3H), 2.80-2.78 (m, 1 H), 0.70 (m, 2H)₁ 0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₃₃H₂₇N₅O₃S requires: 574.66. Found 574.19

HPLC Tr (min), purity %: 3.15, 98%

Example 24

Intermediate E (100 mg) and 1~(tert-butyl)-3-methyl-1 H-pyrazole-5-carbonyI chloride (50 mg) was dissolved in pyridine (2 mL) and the reaction mixture was stirred at 6O⁰C for 30 min. The reaction was quenched with water and extracted with EtOAc (20 mL). The solvent was evaporated and the residue was purified with preparative HPLC (0% to 95% water/ Acetonitrile) to afford 24 (25 mg, 15%).

¹H-NMR (DMSO₁ 300 MHz): δ 9.64 (s, 1 H), 8.54 (d, J = 4.2 Hz, 1 H), 7.76 (d, J = 7.5 Hz, 1 H)₁ 7.66 (s, 1 H), 7.57 (d, J = 8.7 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1 H), 7.07 (t, J = 7.5 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.83-6.81 (m, 1 H)₁ 6.54 (s, 1 H), 4.91 (me, 1 H), 3.20-3.10 (m, 3H), 2.81-2.80 (m, 1 H), 2.44 (s, 3H), 1.60 (s, 9H)₁ 0.70 (m, 2H)₁ 0.56 (m, 2H).

LCMS m/z [M+H]⁺ C₃₂H₃₃N₅O₃S requires: 568.70. Found 568.11

HPLC Tr (min), purity %: 3.44, 98%

Example 25

To a 50 mL flask containing 20 mL of DMF was added 1 mL of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of quinoxaline-5-carboxyltc acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitriie) to afford 25 (26.7 mg, 54%). ¹H-NMR (DMSO, 300 MHz): δ 9.04-9.02 (m, 2H), 8.49 (d, J = 3.9 Hz, 1 H), 8.31 (d, J = 6.0 Hz, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 7.94 (t, J - 7.2 Hz, 1 H), 7.73 (d, J = 6.9 Hz, 1 H), 7.62-7.57 (m, 2H), 7.22 (t, J = 8.4 Hz, 1 H), 7.06 (t, J = 6.6 Hz, 1 H)₁ 6.98 (d, J = 7.8 Hz, 2H), 6.80 (d, J = 7.5 Hz, 1 H), 4.83 (me, 1 H), 3.18-3.06 (m, 3H), 2.77-2.75 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+Hj⁺ C₃₂H₂₅N₅O₃S requires: 560.64. Found 560.08 HPLC Tr (min), purity %: 3.36, 98%

Example 26

To a 50 mL flask containing 20 imL of DMF was added 1 mL of oxalyl chloride siowiy and stirred for 10 min at RT. 100 mg of the carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of P was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 26 (26.7 mg, 54%).

¹H-NMR (DMSO, 300 MHz): δ 8.52 (d, J = 3.9 Hz, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.64-7.43 (m, 3H), 7.24 (t, J = 7.5 Hz, 1 H)₅ 7.15 (t, J = 8.1 Hz, 1 H)₁ 7.08 (t, J = 7.2 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 4.86-4.81 (m, 1 H), 3.34-3.04 (m, 3H), 2.84-2.78 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+H]⁺ C₃₀H₂₂F₄N₄O₃S requires: 595.58. Found 595.00 HPLC Tr (min), purity %: 3.33, 98% Example 27

To a 50 mL flask containing 20 mL of DMF was added 1 ml_ of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of i-Methyl-I H-indazole-3-carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 27 (32 mg, 43%).

¹H-NMR (DMSO, 300 MHz): δ 10.37 (s, 1 H), 8.50 (s, 1 H), 8.10 (d, J = 6.9 Hz, 1 H), 7.72-7.64 (m, 4H), 7.40 (s, 1 H), 7.26-7.23 (m, 2H), 7.04-6.80 (m, 4H), 4.85 (me, 1 H), 4.12 (S, 3H), 3.22-3.10 (m, 3H), 2.78-2.70 (m, 1 H)₁ 0.66 (m, 2H)₁ 0.52 (m, 2H). LCMS m/z [M+H]⁺ C₃₂H₂₇N₅O₃S requires: 561.65. Found 562.04 HPLC Tr (min), purity %: 3.46, 98% Example 28

To a 50 mL flask containing 20 rriL of DMF was added 1 mL of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of 1-(2-Methyl-benzoy!)-piperidtne-4-carboxylic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 28 (51 mg, 65%).

¹H-NMR (DMSO, 300 MHz): δ 10.02 (s, 1 H)₁ 8.54 (d, J = 4.2 Hz, 1 H)₁ 7.75 (d, J = 8.4 Hz, 1 H), 7.64 (s, 1 H), 7.37 (d, J = 8.1 Hz, 2H), 7.31-7.10 (m, 3H), 7.08-7.03 (m, 2H), 6.92 (d, J = 7.5 Hz, 1 H), 6.78 (d, J = 6.9 Hz, 1H), 4.85 (me, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 3.43-2.99 (m, 4H), 2.95-2.79 (m, 1 H), 2.49 (s, 3H), 2.18 (d, J = 10.8 Hz, 2H), 1.86 (d, J = 11.4 Hz, 2H)₁ 1.64-1.50 (m, 2H), 0.69 (m, 2H), 0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₃₇H₃₆N₄O₄S requires: 633.77. Found 633.92 HPLC Tr (min), purity %: 3.13, 98%

Example 29

To a 50 ml_ flask containing 20 ml_ of DMF was added 1 mL of oxalyi chloride siowly and stirred for 10 min at RT. 100 mg of 2-Methyi-2H-pyrazole-3-carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitriie) to afford 29 (29mg, 46%).

¹H-NMR (DMSO, 300 MHz): δ 10.23 (s, 1 H), 8.54 (d, J = 3.9 Hz, 1 H), 7.77 (d, J = 6.9 Hz, 1 H)₁ 7.66 (s, 1 H), 7.52 (d, J = 7.8 Hz, 2H)₁ 7.26 (t, J = 6.6 Hz, 1 H), 7.08 (t, J = 7.8 Hz, 1 H), 6.99-6.91 (m, 3H), 6.82 (d, J = 1.2 Hz, 1 H), 4.87 (me, 1 H), 4.03 (s, 3H), 3.22-3.10 (m, 3H)₁ 2.83-2.80 (m, 1 H), 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+Hf C₂₈H₂₅N₅O₃S requires: 512.59. Found 512.12

HPLC Tr (min), purity %: 2.95, 98% Example 30

To a 50 tnL flask containing 20 mL of DMF was added 1 ml_ of oxaly! chloride slowly and stirred for 10 min at RT. 100 mg of the benzoic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of Q was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 30 (10 mg, 8.5%).

¹H-NMR (DMSO, 300 MHz): δ 10.28 (s, 1 H), 8.54 (d, J = 3.6 Hz, 1 H), 7.84 (d, J = 7.5 Hz, 3H), 7.62-7.43 (m, 5H), 7.24 (d, J = 9.6 Hz₁ 1 H)₁ 6.95 (d, J = 7.5 Hz, 2H), 6.76 (d, J = 7.8 Hz, 1 H), 4.83 (me, 1 H), 3.15-3.07 (m, 3H), 2.77-2.76 (m, 1 H), 0.65 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+H]⁺ C₃₀H₂₄BrN₃O₃S requires: 587.50. Found 587.99

HPLC Tr (min), purity %: 2.55, 98% Example 31

To a 50 ml_ flask containing 20 mL of DMF was added 1 mL of oxalyl chloride slowfy and stirred for 10 min at RT. 100 mg of 2-bromo-5-pyridinecarboxylic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of intermediate E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT. The solvent was then evaporated under vacuum, water added and the precipitate filtered. The precipitate was then dissolved in azetidine (1 mL) and stirred at RT for 2h. Volatiles were removed under reduced pressure and the residue dissolved in CH₃CN and water and purified with prep HPLC

{0% to 95% water/ Acetonitrile) to afford 31 (24.6 mg, 20%).

¹H-NMR (DMSO, 300 MHz): δ 10.15 (s, 1 H), 8.55 (s, 1 H), 8.09 (d, J = 9.3 Hz, 1 H)₁ 7.77 (d, J = 7.5 Hz₁ 1 H), 7.66 (s, 1 H)₁ 7.53 (d, J = 8.7 Hz, 1 H), 7.25 (t, J = 7.5 Hz, 1 H), 7.07 (t, J = 7.5 Hz₁ 1 H)₁ 6.97 (d, J = 7.8 Hz₁ 1 H), 6.82 (d, J = 9.1 Hz, 1 H)₁ 6.58 (d, J = 9.6 Hz, 1 H), 4.87 (me, 1 H)₁ 4.16-3.97 (m, 5H), 3.21-3.11 (m, 3H), 2.81-2.80 (m, 1 H), 2.39-2.36 (m, 1 H)₁ 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+Hf C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.14

HPLC Tr (min), purity %: 2.58. 98%

Example 32

To a 50 ml_ flask containing 20 mL of DMF was added 1 mL of oxalyi chloride slowly and stirred for 10 min at RT. The 2,2-diphenyl-acetic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of intermediate C was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with NH₄OH (1 mL). Volatiles were removed under reduced pressure and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 32 {40 mg, 20%).

¹H-NMR (DMSO₁ 300 MHz): δ 8.41 (d, J = 3.9 Hz, 1 H), 7.60-7.52 (m, 1 H), 7.44 (s, 1 H), 7.37-7.34 (m, 3H), 7.27-7.15 (m, 4H), 6.95-6.82 (m, 3H), 6.50 (d, J = 7.5 Hz, 2H), 5.07 (s, 1 H), 4.59-4.55 (m, 1 H), 3.25-3.20 (m, 1 H), 3.05-2.96 (m, 1 H), 2.89-2.76 (m, 1 H), 0.65 (m, 2H)₁ 0.51 (m, 2H).

LCMS m/z [M+Hf C₃₀H₂₆N₂O₂S requires: 479.60. Found 479.10

HPLC Tr (min), purity %: 2.63, 98%

Example 33

intermediate C {100 mg) and naphthalene-2-carbonyi chloride (50 mg) was dissolved in pyridine (2 mL) and the reaction mixture was stirred for 30 min. The reaction was quenched with water and extracted with EtOAc (20 mL). The solvent was evaporated and the residue was purified with preparative HPLC (0% to 95% water/ Acetonitrile) to afford 33 (70 mg, 65%). ¹H-NMR (DMSO, 300 MHz): δ 8.52 (d, J = 3.9 Hz₁ 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.77- 7.61 (m, 6H), 7.48-7.40 (m, 2H), 7.15 (d, J - 7.2 Hz, 1 H), 6.92 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 7.8 Hz, 1 H), 4.87 (me, 1 H), 4.01 (s, 2H)₁ 3.36-3.04 (m, 3H)₁ 2.80-2.74 (m, 1 H), 0.66 (m, 2H), 0.52 (m, 2H). LCMS m/z [M+H]⁺ C₂₇H₂₂N₂O₂S requires: 439.54. Found 439.13 HPLC Tr (min), purity %: 3.21 , 98%

Example 34

To a 50 mL flask containing 20 ml_ of DMF was added 1 ml_ of oxaiyi chloride slowly and stirred for 10 min at RT. 100 mg of the phenyl sulfonic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 34 (32 mg, 43%).

¹H-NMR (DMSO, 300 MHz): δ 10.39 (s, 1 H), 8.47 (d, J = 3.9 Hz, 1 H)₁ 7.68 (d, J = 6.9 Hz, 1 H), 7.63-7.43 (m, 6H), 7.19 (t, J - 7.5 Hz, 1 H), 6.94 (t, J = 1.2 Hz₇ 2H), 6.80 (s, 1 H), 6.66-6.60 (m, 1 H), 4.76 (me, 1 H), 3.11-2.96 (m, 3H), 2.77-2.72 (m, 1 H), 0.64 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+H]⁺ C₂₉H₂₅N₃O₄S₂ requires; 544.66. Found 544.09

HPLC Tr (min), purity %: 2.35, 98% Example 35

To a 50 mL flask containing 20 mL of DMF was added 1 ml of oxalyl chloride slowly and stirred for 10 min at RT. 100 mg of benzo[1 ,3]dioxo!e-5-carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of C was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 2 h at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 35 (67 mg, 86%).

¹H-NMR (DMSO, 300 MHz): δ 8.48 (d, J = 3.3 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.60 (s, 1 H), 7.21 (t, J = 7.2 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1 H), 6.81 (d, J = 7.8 Hz₁ 1 H), 6.64 (d, J = 8.1 Hz₁ 1 H), 6.53 (s, 1 H), 6.36 (d, J = 8.4 Hz, 1 H), 5.92 (s, 2H), 4.79 (me, 1 H), 3.14 (m, 3H), 2.78-2.72 (m, 1 H), 0.64 (m, 2H), 0.51 (m, 2H).

LCMS m/z [M+Hf C₂₄H₂₀N₂O₄S requires: 433.49. Found 433.05

Example 36

To a 50 mi_ flask containing 20 mi_ of DMF was added 1 mL of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of 4-thiophen-2-y!-benzotc acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT, Then 50mg of C was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 2 h at RT and quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue dissolved in CH₃CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 36 (31.8 mg, 25 %). ¹H-NMR (DMSO, 300 MHz): jδ 8.55 (d, J = 3.9 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 7.67 (S, 1 H), 7.55 (d, J = 4.8 Hz, 1 H), 7.50-7.47 (m, 3H), 7.26 (d, J = 7.5 Hz, 1 H), 7.11- 7.00 (m, 4H)₁ 6.87 (d, J = 9.1 Hz, 1 H), 4.88 (me, 1 H), 3.29-3.06 (m, 3H), 2.86-2.78 (m, 1 H), 0.70 (m, 2H), 0.57 (m, 2H). LCMS m/z [M+H]⁺ C₂₇H₂₂N₂O₂S₂ requires: 471.61. Found 471.00 HPLC Tr (min), purity %: 2.59, 98%

Example 37

Compound 1 (15 mg) and pyrrolidine (25 mg) were dissolved in DMF (1 mL) and triethylamine (0.5 mL). The reaction mixture was stirred at 7O⁰C for 16 h. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrϋe) to afford 37 (7.6 mg, 26%). ¹H-NMR(DMSO₅300 MHz): δ 8.54 (d, J= 3.6 Hz, 1H), 8.12 (d, J =3.6 Hz, 1H), 7.81 (d, J - 7.5 Hz, 1 H), 7.76 (d, J - 7.5 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1 H)₁7.26 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz₁1H), 6.84 (d, J = 6.9 Hz, 1H), 6.76 (d, J - 6.3 Hz, 1H), 4.82 (me, 1H), 3.91-3.37 (m, 4H), 3.37-2.81 (m, 5H), 0.68 (me, 2H), 0.55 (me, 2H).

LCMS m/z [M+H]⁺ C₃₃H_3IN₅O₃S requires: 577.21. Found 578.23 HPLC Tr (min), purity %: 3.01 , 95%

Examples 38-46 follow the procedure for example 37 except substituting pyroliidine with the appropriate amine. Example 38

Yield 83%

¹H-NMR(DMSO, 300 MHz): δ 10.57 (s, 1H), 8.54 (d, J= 3.9 Hz, 1H), 8.18 (d, J = 4.5 Hz, 1H), 7.75 (t, J = 8.1 Hz, 2H), 7.65 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.27 (t, J = 7.5Hz, 1H), 7.10 (t, J= 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.75 (t, J= 5.1 Hz, 1H), 5.44 (s, 1H), 5.27 (s, 1H), 4.88 (me, 1H), 3.84-3.73 (m, 3H), 3.20-3.10 (m, 4H), 2.82- 2.79 (m, 1H)₁2.20-2.12 (m, 1H), 0.70 (m, 2H), 0.55 (m, 2H). LCMS [M+Hf C₃₃H₃₀FN₅O₃S requires 595 69 Found 595 23 HPLC Tr (mm), purity % 3 21 , 98% Example 39

Yield 87%

¹H-NMR (DMSO, 300 MHz) δ 10 57 (s, 1 H), 8 49 (d, J = 3 9 Hz, 1 H), 8 13 (d, J = 5 1 Hz, 1 H)₁ 7 72 (t, J = 8 1 Hz, 2H)₁ 7 60 (s, 1 H), 7 44 (d, J - 8 1 Hz₁ 1 H), 7 22 (t, J ~ 7.5Hz, 1 H), 7 05 (t, J = 8 1 Hz, 1 H), 6.94 (d, J - 8 1 Hz, 1 H), 6.67 (t, J = 5 1 Hz, 1 H), 5 38 (s, 1 H), 5 21 (s, 1 H), 4 83 (me, 1 H), 3.74-3 62 (m, 3H), 3 15-3 10 (m, 4H), 2 79- 2 70 (m, 1 H), 2 16-2 12 (m, 1 H), 0 65 (m, 2H), 0.50 (m, 2H)

LCMS m/z [M+H]⁺ C₃₃H₃₀FN₅O₃S requires 595 69 Found 595 23

HPLC Tr (mm), purity % 3 21 , 98%

Example 40

Yield 96%

¹H-NMR (DMSO, 300 MHz): δ 10.52 (s, 1 H), 8.49 (d, J = 3.9 Hz₁ 1 H)₁ 8.08 (d, J = 5.1 Hz₁ 1 H), 7.72 (t, J = 7.8 Hz, 2H), 7.61 (s, 1 H), 7.43 (d, J = 8.1 Hz, 2H), 7.22 <t, J = 7.8Hz, 1 H), 7.05 (t, J = 7.5Hz, 1 H), 6.94 (d, J = 7.8 Hz, 2H), 6.71 (t, J = 7.5 Hz, 1 H), 4.83 (me, 1 H), 4.21 (dd, J = 6.0, 12.3 Hz, 1 H)₁ 3.66-3.37 (m, 2H), 3.16-3.00 (m, 3H), 2.76-2.48 (m, 1 H), 2.03-1.97 (m, 1 H), 1.85-1.72 (m, 1 H), 1.70-1.67 (m, 1 H), 1.54- 1.50 (m, 1 H), 1.12 (d, J = 6.3 Hz, 1 H), 0.65 (m, 2H), 0.50 (m, 2H).

LCMS m/z [M+H]⁺ C₃₄H₃₃N₅O₃S requires: 591.72. Found 591.68

HPLC Tr (min), purity %: 3.25, 98%

Example 41

Yield 98%

¹H-NMR(DMSO, 300 MHz): δ 10.43 (s, 1H), 8.54 (d, J= 3.9 Hz, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.65 (s, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.27 (t, J= 7.5 Hz, 1H), 7.10 (t, J= 7.5 Hz, 1H), 6.98 (d, J= 8.1 Hz, 2H), 6.85 (d, J - 6.9 Hz, 1H), 6.74 (t, J = 7.2 Hz, 1H), 4.87 (me, 1H)₁4.31 (s, 1H), 3.12- 3.10 (m, 3H), 2.81-2.77 (m, 1H), 1.89-1.83 (m, 4H)₁1.75-1.68 (m, 2H), 0.70 (m, 2H)₁ 0.55 (m, 2H).

LCMS m/z [M+Hf C₃₅H₃₅N₅O₃S requires: 622.75. Found 622.18

HPLC Tr (min), purity %: 3.21, 98% Example 42

Yield 34%

¹H-NMR (DMSO, 300 MHz): δ 10.55 (s, 1H), 8.55 (d, J= 3.6 Hz, 1H)₁8.23 (d, J= 3.6

Hz₅1H), 7.75 (t, J = 7.2 Hz, 2H)₁7.66 (s, 1H)₁7.49 (d, J = 8.1 Hz, 1H), 7.27 (t, J =

7.8 Hz, 1H), 7.10 (t, J= 8.1 Hz, 1H)₁7.00 (d, J= 8.1 Hz₁1H), 6.87 (t, J = 6.9 Hz, 1H), 5.55 (me, 1H), 3.15-3.05 (m, 3H)₁2.82-2.75 (m, 1H), 3.37-2.81 (m, 5H), 0.69 (m, 2H),

0.55 (m, 2H). LCMS m/z [M+Hf C₃₄H₃₀F₃N₅O₃S requires: 646.69. Found 646.20

HPLC Tr (min), purity %: 3.25, 98%

Example 43

Yield 95%

¹H-NMR(DMSO, 300 MHz): δ 10.49 (s, 1H), 8.54 (d, J - 3.3 Hz, 1H), 8.11 (d, J =3.3 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H)₁7.65 (s, 2H), 7,47 (d, J = 7.5 Hz, 2H), 7.27 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.1 Hz, 2H), 6.86 (me, 1H), 6.72- 6.68 (m, 1H), 4.87 {me, 1H), 4.42 (s, 1H), 3.19-3.11 (m, 3H)₁2.0 (s, 1H), 2.01-1.83 (m, 2H), 0.70 (m, 2H), 0.55 (m, 2H).

LCMS m/z [M+Hf C₃₅H₃₅N₅O₃S requires: 622.75. Found 622.18 HPLC Tr (min), purity %: 3.21 , 98% Example 44

Yield 94%

¹H-NMR(DMSO, 300 MHz): δ 10.59 (s, 1H), 8.54(Ci₁J = S-SHz₅1H)₁8.13 (d, J = 4.8 Hz, 1H)₁7.77 (d, J - 7.5 Hz₁2H), 7.66 (s, 1H), 7.49 (d, J = 7.8 Hz, 2H), 7.25 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz₁1H), 6.99 (d, J = 8.1 Hz₁2H), 6.85 (Cl₁ J = 6.9 Hz, 1H), 6.75 (t, J = 7.2 Hz₁1H), 4.87 (me, 1H)₁4.30 (s, 1H), 3.21-3.11 (m, 7H), 2.81- 2.77 (m, 1H)₁1.89-1.83 (m, 2H), 0.70 <m, 2H)₁0.55 (m, 2H).

LCMS m/z [M+Hf C₃₃H₃₁N₅O₄S requires: 593.70. Found 593.68 HPLC Tr (min), purity %: 2.98, 98% Example 45

Yield 38% ¹H-NMR (DMSO, 300 MHz): δ 10.47 (s, 1H), 8.51 (d, J- 3.3 Hz, 1H)₁8.26 (d, J = 3.3

Hz, 1H)₁7.75 (d, J = 7.5 Hz₁2H), 7.63 (s, 1H)₁7.23 (t, J = 7.8 Hz, 1H), 7.08 (t, J - 7.2 Hz, 1H), 6.88-6.85 (m, 2H), 6.77 (d, J = 7.5 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H)₁ 6.28 (d, J = 8.7 Hz₁1H), 4.92 (me, 1H)₁4.32-4.20 (m, 4H)₁4.14 (s, 1H), 3.19-3.10 (m, 3H)₁2.79 (s, 1H)₁0.69 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+Hj⁺ C₃₂H₂₈FN₅O₃S requires: 582.66. Found 582.54

HPLC Tr (min), purity %: 3.15, 98%

Example 46

Yield 75%

¹H-NMR (DMSO₁300 MHz): δ 10.45 (s, 1H)₁8.55 (s, 1H), 8.11 (d, J= 3.3 Hz, 1H), 7.77 (d, J - 7.5 Hz, 2H), 7.65 (S₁1H), 7.48 (d, J = 8.1 Hz, 2H)₁7.26 (t, J = 8.1 Hz₁ 1 H)₁7.07-6.93 (m, 3H), 6.74 (t, J = 6.9 Hz₁2H)₁4.87 (me, 1 H), 4.33 (S₁1 H), 3.93 (t, J =6.9 Hz, 2H), 3.11-3.05 (m, 3H), 2.81 (s, 1H)₁2.30 (t, J = 7.2 Hz₁1H), 2.08 (s, 1H)₁ 0.70 (m, 2H), 0.55 (m, 2H).

LCMS m/z [M+H]⁺ C₃₂H₂₉N₅O₃S requires: 564.67. Found 564.31 HPLC Tr (min), purity %: 2.53, 98% Example 47

To a 50 mL flask containing 20 ml_ of DMF added 1 mL of oxalyl chloride sϊowly, an orange solution formed after the addition. 100mg of 2-methyl-4-methoxybenzoic acid was dissolved in 2 mL of the above orange solution and stirred for 5mins at room temperature. Then 50mg of the intermediate E was dissolved in 1 ml pyridine and then this pyridine solution was added to the above orange carboxylic acid solution. Reaction was finished in 5mins at room temperature and was quenched with 1 mL NH₄OH. The solvent was then evaporated under vacuum and the residue was dissolved in CH₃CN and water and purified with prep HPLC to afford 47 (19mg, 28%).

¹H-NMR (DMSO₁ 300 MHz): δ 10.21 (s, 1 H), 8.54 (d, J = 3.3 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1H)₁ 7.66 (S₁ 1 H)₁ 7.51 (d, J = 7.8 Hz₁ 1H)₁ 7.40 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 7.8 Hz, 1 H), 7.10 (t, J = 7.8 Hz, 1H), 6.96 (d, J = 8.1 Hz, 3H), 6.83-6.80 (m, 3H)₁ 4.88-4.86 (m, 1H), 3.76 (s, 3H)₁ 3.22-3.12 (m, 4H)₁ 2.85-2.75 (m, 1H), 2.33 (s, 3H), 0.70 (m, 2H), 0.56 (m, 2H).

LCMS m/z [M+H]^* C₃₂H₂₉N₃O₄S requires: 552.70. Found 552.05. HPLC Tr (min), purity %: 3.23, 95%. HPLC Tr (min), purity %: 3.23, 95%. Example 48

48

i. HATU, OiPEA, DMF, amine

Mixed N (12mg, 0.02mmo!) with DMF (30OuL), DIPEA (5.5uL, O.OSmmoi) and HATU (10mg, 0.025mmo!). Added 2-aminomethylthiophene (0.026mmol). Stirred for 3 hrs. Diluted reaction with acetonitπie and water and purified with prep HPLC to give 48.

¹H NMR (300MHz, CD₃OD): δ 8.16 (m, 1 H)₁ 8.02 (m, 1 H), 7.82 (m, 1 H)₁ 7.61 (s, 1 H), 7.51 (m, 2H), 7.29 (m, 2H)₁ 7.09-6.94 (m, 6H), 6.83 (m, 1 H), 5.02 (m, 1 H)₁ 4.73 (S₁ 2H), 3.58 (m, 5H), 3.14 (m, 2H)₁ 2.07 (m, 4H).

LC/MS (m/e): 634.1 [M+Hf

The following examples 49-62 were prepared from intermediate N using the same procedure as described for 48 above except substituting the appropriate amine for instead of 2-aminomethyl thiophene.

Example 49

¹H NMR (300MHz₁ CD₃OD): δ 8.13 (m, 1 H), 7.83 (m, 1 H)₁ 7.66 (m, 1 H), 7.59 (s, 1 H), 7.51 (m, 2H), 7.29 (m, 1 H), 7.09 (m, 3H), 6.87 (m, 1 H), 6.66 (m, 1H), 5.02 (m, 1 H), 3.86 (m, 2H)₁ 3.65 (m, 2H)₁ 3.41 (m, 5H), 3.12 (m, 2H), 1.90 (m, 4H)₁ 2.02 (m, 8H). LC/MS (m/e): 592.2 [M+Hf

Example 50

¹H NMR (300MHz, CD₃OD): δ 8.77 (m, 1H)₁8.49 <m 1H), 8.16 (m, 1H), 8.02 (m, 2H), 7.90 (m, 1H), 7.80 (m, 1H), 7.74 (s, 1H), 7.53 (m, 2H), 7.27 (m, 1H), 7.09 (m, 3H), 6.99 (m, 1H), 6.87 (m, 1H), 5.02 (m, 1H), 4.73 (s, 2H), 3.58 (m, 5H), 3.19 (m, 2H), 2.07 (m, 4H).

LC/MS (m/e): 629.1 [M+H]⁺ Example 51

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.80 (m, 1H), 7.73 (S, 1H), 7.52 (m, 2H), 7.28 (m, 1H), 7.11 (m, 3H), 6.99 (m, 1H)₁6.87 (m, 1H), 5.02 (m, 1H), 4.56 (m, 1H), 3.58 (m, 5H)₁3.19 (m, 2H), 2.07 (m, 4H), 1.51 (d, J=7.2Hz, 3H).

LC/MS (m/e): 609.2 [M+H]⁺ Example 52

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.67 (s, 1H), 7.53 (m, 3H), 7.27 (m, 1H), 7.11 (m, 3H), 6.99 (m, 1H), 6.88 (m, 1H), 5.02 (m, 1H), 4.88 (s, 2H), 3.58 (m, 5H), 3.18 (m, 2H), 2.08 (m, 4H).

LC/MS (m/e): 635.1 [M+H]⁺

Example 53

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.82 (m, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 7.09 (m, 3H), 6.99 (m, 1H), 6.87 (m, 1H), 5.02 (m, 1H)₁ 3.84 (m, 2H), 3.58 (m, 5H), 3.36 (m, 2H), 3.17 (m, 2H), 2.07 (m, 4H).

LC/MS (m/e): 645.2 [M+H]⁺

Example 54

¹H NMR (300MHz₁ CD₃OD): δ 8.41 <m 1H), 8.16 (m, 2H), 8.00 (m, 3H), 7.89 <m, 1H), 7.54 (m, 2H), 7.33 (m, 2H), 7.13 (m, 3H), 6.99 (m, 1H), 6.92 (m, 1H), 5.02 (m, IH), 3.58 (m, 5H), 3.19 (m, 2H), 2.07 (m, 4H).

LC/MS(m/e): 615.2 [M+Hf Example 55

¹H NMR (300MHz, CD₃OD): δ 8.18 <m, 1H), 8.01 (m, 1H), 7.82 (m, 1H), 7.53 (m, 2H), 7.45 (S₁1H), 7.29 (m, 1H), 7.12 (m, 3H), 7.00 (m, 1H), 6.87 (m, 1H), 5.02 (m, 1H), 3.58 (m, 5H), 3.33 (m, 6H), 3.18 (m, 2H), 2.07 (m, 4H).

LC/MS (m/e): 566.2 [M+H]⁺ Example 56

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.82 (m, 1H), 7.64 (S₁1H)₁ 7.52 (m, 2H), 7.29 (m, 1H), 7.08 (m, 3H), 7.00 (m, 1H), 6.87 (m, 1H), 5.02 (m, 1H), 3.70 (S, 2H), 3.58 (m, 5H), 3.08 (m, 2H), 2.08 (m, 4H), 1.42 (s, 6H). LC/MS (rn/e): 610.2 [M+Hf

Example 57

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.00 (m, 1H), 7.83 (m, 1H), 7.68 (s, 1H), 7.50 (m, 2H), 7.29 (m, 1H), 7.09 (m, 3H), 7.00 (m, 1H), 6.85 (m, 1H), 5.00 (m, 1H), 4.57 (m, 1H)₁3.96-3.76 (m, 3H), 3.58 (m, 5H), 3.17 (m, 2H), 2.30 (m, 1H), 2.07 (m, 4H).

LC/MS (m/e): 608.2 [M+Hf

Example 58

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.83 (m, 1H), 7.64 (s, 1H), 7.52 (m, 2H), 7.30 (m, 1H), 7.09 (m, 3H), 7.00 (m, 1H), 6.88 (m, 1H), 5.02 (m, 1H), 4.65 (m, 1H), 4.51 (m, 1H), 3.72 (m, 1H), 3.63 (m, 1H)₁3.58 (m, 5H), 3.12 (m, 1H), 2.07 (m, 4H).

LC/MS (m/e): 584.1 [M+H]⁺ Example 59

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.84 (m, 1H), 7.51 (m, 3H), 7.29 (m, 1H), 7.11 (m, 3H), 7.00 (m, 1H), 6.88 (m, 1H)₁5.03 (m, 1H), 4.80 (m, 1H), 4.36 (m, 3H), 3.99 (m, 1H)₁3.58 (m, 5H), 3.35 (m, 3H), 3.17 (m, 2H), 2.07 (m, 4H). LC/MS (m/e): 608.2 [M+H]⁺ Example 60

¹H NMR (300MHz, CD₃OD): δ 8.17 (m, 1H), 8.02 (m, 1H), 7.82 (m, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 7.09 (m, 3H), 7.00 (m, 1H), 6.87 (m, 1H), 5.02 (m, 1H), 3.60 (m, 7H), 2.56 (m, 2H), 2.07 (m, 4H). LC/MS (m/e): 609.2 [M+Hf

Exampie 61

¹H NMR (300MHz, CD₃OD): δ 8.17 <m, 1H), 8.02 (m, 1H), 7.83 (m, 1H), 7.64 (s, 1H), 7.52 (m, 2H)₅7.29 <m, 1H), 7.12 (m, 3H)₁7.00 (m, 1H), 6.88 (m, 1H), 5.01 (m, 1H), 3.60 (m, 6H), 3.17 (m, 1H), 2.08 (m, 4H).

LC/MS (m/e): 538.2 [M+H]⁺ Example 62

¹H NMR (300MHz, CD₃OD): δ 8.16 (m, 1H), 8.03 (m, 1H), 7.83 (m, 1H), 7.70 (s, 1H), 7.53 (m, 3H)₁7.30 (m, 1H), 7.11 (m, 3H)₁6.99 (m, 1H)₁6.89 (m, 1H), 5.02 (m, 1H), 4.85 (S₁2H), 3.70 (s, 3H), 3.58 (m, 6H), 3.18 (m, 2H), 2.08 (m, 4H).

LC/MS (m/e): 632.1 [M+H]⁺ Example 63

Intermediate R (15 mg) and 3-fiuoroazetidine (6 mg) were dissolved in DMF (1 m!_). To the above solution CuI (5mg) and Cesium Carbonate (25mg) were added. The reaction mixture was stirred at 9O⁰C overnight. Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitrile) to afford 63 (6 mg, 40%) as a yellow powder.

¹H-NMR (DMSO, 300 MHz): δ 8.92 (s, 1 H), 8.40 (d, J = 4.2 Hz, 1 H), 7.75 (t, J = 7.2 Hz, 1 H), 7.62 (t, J = 8.1 Hz₁ 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 7.22 (s, 2H), 7.13 (d, J = 7.8 Hz, 1 H), 7.10-7.03 (m, 2H), 6.80 (s, 1 H), 6.69 (d, J = 7.2 Hz₁ 1 H), 5.26 (s, 1 H), 4.82 (d, J = 8.1 Hz, 1 H), 4.38-4.21 (m, 4H), 3.29-3.18 (m, 3H), 2.93 (d, J = 12.0 Hz, 1 H), 2.88 (s, 1 H), 0.85-0.80 (m, 2H), 0.65 (me, 2H). LCMS m/z [M+Hf C₃₂H₂₈FN₅O₃S requires: 581.66. Found 581.87 HPLC Tr (min), purity %: 3.32, 98%

Example 64

Intermediate T (20 mg) and 3,3-difluoroazetidine (30 mg) were dissolved in DMF (1 mL) and triethylamine (0.5 mL). The reaction mixture was stirred at 9O⁰C overnight.

Volatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitriie) to afford 64 (6 mg, 30%) as a yellow powder.

¹H-NMR (DMSO₁ 300 MHz): δ 10.53 (s, 1 H), 8.57 (d, J - 4.2 Hz, 1 H), 8.45 (d, J = 4.2 Hz, 1 H), 7.90 (d, J = 7.2 Hz, 1 H), 7.72 (d, J = 7.2 Hz₇ 2H), 7.62 (s, 1 H), 7.54 (d, J = 4.8 Hz, 1 H)₁ 7.23 (t, J = 7.8 Hz, 1 H), 7.11 (d, J = 4.2 Hz, 1 H), 6.98-6.82 (m, 2H), 6.75 (d, J = 7.2 Hz, 1 H)₁ 4.84 (d, J - 7.8 Hz, 1 H), 4.32-4.20 (m, 4H), 3.28-3.04 (m, 3H}, 2.88-2.80 (rπ, 1 H), 0.70 (m, 2H), 0.55 (m, 2H) LCMS m/z [M+H]⁺ C₃₂H₂₆F₃N₅O₃S requires: 617.64. Found 617.86 HPLC Tr (min), purity %: 3.13, 98%

Example 65

Intermediate U (15 mg) was dissolved in Pyrrolidine (1 mL). The reaction mixture was stirred at RT overnight. Voiatiies were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitriie) to afford 65 (7.7 mg, 48%) as a yellow powder.

¹H-NMR (DMSO, 300 MHz): δ 8.58 (d, J = 9.1 Hz₁ 1 H), 7.92 (s, 1 H), 7.70 (s, 1 H), 7.63 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 7.2 Hz, 1 H), 6.31-6.28 (m, 3H), 6.04 (d, J = 8.4 Hz₁ 1 H), 4.48 (me, 1 H), 4.32-4.20 (m, 5H), 3.91-3.37 (m, 4H), 3.37-2.81 (m, 2H), 2.35-2.30 (m, 1 H), 1.82 (s, 3H), 0.70 (m, 2H), 0.55 (m, 2H)

LCMS m/z [M+Hf C₃₃H₃₂N₆O₃S requires: 592.71. Found 592.93 HPLC Tr (min), purity %: 3.10, 98%

Example 66

To a 50 mL flask containing 20 mL of DMF was added 1 ml of oxalyl chloride slowly, an orange solution formed after the addition. 100mg of 3-Chloro-4- Pyridinecarboxylic Acid was dissolved in 2 mL of the above orange solution and stirred for 5mins at room temperature. Then 100 mg of the intermediate P was dissolved in 1 mL pyridine and then this pyridine solution was added to the above orange carboxylic acid solution. The reaction was finished in 5 min at room temperature. The solvent was then evaporated under vacuum and 0.02g of the residue was dissolved in pyrrolidine (4 rnl) and stirred for 2 h. Volatiles were removed under vacuum and the resulting residue dissolved in CH₃CN and water and purified with prep HPLC to afford 66 as a off-white powder (12.2 mg, 43%).

¹H-NMR (DMSO, 300 MHz): d 10.67 (s, 1 H), 8.51 (d, J = 3.9 Hz, 1 H), 8.13 (d, J = 5.7 Hz, 1 H), 7.77-7.30 (m, 3H), 7.63-6.92 {m, 3H), 6.90 (d, J = 7.5, 1 H), 6.73 (m, 1 H), 4.81 (m, 1 H), 3.34-2.79 (m, 7H), 1.84 (s, 4H), 0.71 (m, 2H), 0.55 (m, 2H). LCMS m/z [M+Hf C₃₃H₃₀FN₅O₃S requires: 595.21. Found 596.09 HPLC Tr (min), purity %: 2.09, 98%

Example 67

Intermediate U {15 mg) was dissolved in DMF (1 ml_) and triethyiamine (0.1 mL). The reaction mixture was stirred at 9O⁰C overnight. Voiatiles were removed under reduced pressure at 4O⁰C and the resulting residue was purified by preparative HPLC (0% to 95% water/ Acetonitriie) to afford 67 (1 mg, 5%) as a yellow powder.

¹H-NMR (DMSO, 300 MHz): δ 7.00 (d, J = 9.1 Hz, 1 H), 6.97 (s, 1 H), 6.76 (s, 1 H), 6.70 (d, J = 8.7 Hz, 2H), 6.48 (t, J = 7.8 Hz, 1 H), 6.31 -6.28 (m, 3H), 6.04 (d, J = 8.4 Hz, 1 H), 4.18 (me, 1 H), 4.32-4.20 (m, 4H)₁ 3.28-3.05 (m, 3H), 2.35-2.30 (m, 1 H), 1.82 (s, 3H), 0.70 (m, 2H), 0.56 (m, 2H)

LCMS m/z [M+H]⁺ C₃₂H₂₈F₂N₆O₃S requires: 614.66. Found 614.87 HPLC Tr (min), purity %: 3.12, 98%

Claims

Claims

1. The present invention provides a compound of Formula !:

Formula

wherein A is aryl or heteroaryi;

Ri is alkyl, alkoxy, haloalkyi, aryl, heteroaryi, heterocyclyl, cycloalkyl, said heterocycly! is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxy!, haloalkyi, alkoxy, alkyl, alkoxy- alky!— ,hydroxyl-alkyl— , CN, aiky!-NH— ,,; said aryi or heteroaryi is optionally substituted by one to three substituents independently selected from the group consisting of halo, cyano, nitro, hydroxy!, aikyl, alkoxy, alkyl-NH-, with the proviso that when A is aryl, Ri is not unsubstituted ary!;

R₂ is hydrogen, alkyl, alkoxy, amino, aikyi-NH-, CN, alkyl-SCV-, or halo; R₃ is hydrogen, alkyi, heterocyclyl, heteroaryi, heteroaryl-alkyl-, or cycloalkyl, said aikyl is optionally substituted by one substituent selected from the group consisting of NHb-C(O)--, halo, hydroxyl, NH2-SO2— , alkoxy-alkyl— , heterocyciyl; aryl, heteroaryl, CN, alkyl-NH~ R₄ is hydrogen, or alkyl; or haioaikyl

R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring;

R₅ is hydrogen, aikyl, alkoxy, haioaikyl, or halo; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A is C₆-Ci₀ aryl, or monocyclic 6-membered heteroaryl.

3. The compound of claim 1 wherein A is monocyclic 5-membered heteroaryt or bicyclic 8- to 10-membered heteroaryl.

4. The compound of claim 1 wherein A is a monocyclic 5-membered heteroaryl; Ri is alkyl, or aryl; R₂ is hydrogen, or aikyl; R₃ is cycloalkyl, or alky!; R₄ is hydrogen;

R₅ is hydrogen, or halo.

5. The compound of claim 4 wherein A is thienyl or pyrazolyl group.

6. The compound of claim 1 wherein A is a bicyclic 8- to 10-membered heteroaryl; Ri is alkyl, or hydrogen; R₂ is hydrogen, or aikyl; R₃ is cycloalkyl, or alkyl; R₄ is hydrogen; R₅ is hydrogen, or halo.

7. The compound of claim 6 wherein A is indolyl, indazolyl, or quinoxaiinyl group.

8. A compound of Formula IA:

Formula IA wherein X₁ Y and Z are independently N or CH;

Ri is alkyi, alkoxy, haloatkyl, aryl, heteroaryl, heterocyciy!, said heterocyclyl is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxy!, haloalkyl, alkoxy, alkyl, alkoxy-alkyK and hydroxyl-alkyK said aryl is optionally substituted by one to two substituents independently selected from the group consisting of halo, cyano, nitro and hydroxyl, with the proviso that when X and Y are simultaneously CH, Ri is not unsubstituted aryl;

R₂ is hydrogen, alkyl, aikoxy, or halo;

R₃ is hydrogen, alkyl, heterocyclyl, heteroaryi, heteroaryl-alkyl-, or cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, hydroxyl, NH₂-SO₂--, alkoxy-alkyl-, and heterocyclyl; R₄ is hydrogen, or alky!; R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring;

R₅ is hydrogen, alkyl, alkoxy, haloaikyl, or halo; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein X and Z are CH₁ Y is N.

10. The compound of claim 8 wherein X, Y and Z are CH.

11. The compound of claim 8 wherein X and Z are N, Y is CH.

12. The compound of claim 8 wherein X and Z are CH; Y is N; R₁ is haloaikyl, or heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl-, alkyl, haloaikyl, or hydroxyi-alkyl--; R₂ is hydrogen; R₃ is hydrogen, alkyl, heteroaryl, heteroaryl-alkyl-, or cycloalkyl, said aikyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)--, halo, hydroxyl, NH₂-SO₂--, alkoxy- alkyl-, and heterocyclyl; R₄ is hydrogen, or alkyl; R₃ and R₄ taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring; R₅ is hydrogen, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

13. The compound of claim 12 wherein R₁ is (d-C^haloalkyl, or 4- to 7- membered heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, (d- C₄)alkoxy-(d-C₄)alkyK (d-C^alkyl, (d-C₄)haloalkyl, or hydroxyl-(C_rC₄)a!kyl~; R₃ is hydrogen, (d-C₄)alkyl, 5- to 9-membered heteroaryl, 5- to 9-membered heteroaryi- (Ci-C₄)alkyl— , or (C₃-C₇)cycloalkyi_; said alkyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, hydroxy!, NH₂- SO₂-, (d-C₄)alkoxy-(d-C₄)alkyl", and 4- to 7-membered heterocyclyl; R₄ is hydrogen, or {d-C₄)alkyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

14. The compound of claim 8 wherein X, Y and Z are CH; R₁ is alky!, alkoxy, or heteroaryl; R₂ is hydrogen, or alkoxy; R₃ is cycloalkyl; R₄ and R₅ are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

15. The compound of claim 14 wherein Ri is (Ci-C₄)alkyl, (Ci-C₄)alkoxy, or 5- to 9-membered heteroaryi; R₂ is hydrogen, or (C_rC₄)alkoxy; R₃ is (C₃-C₇)cycioalkyi; R₄ and R₅ are hydrogen.

16. The compound of claim 8 wherein X and Z are N, Y is CH; R₁ is alkyl, alkoxy, or heteocyclyl; R₂ is alkyl; R₃ is cycioalkyl; R₄ and R₅ are hydrogen; or a

pharmaceutically acceptable salt thereof.

17. A compound of Formula IB:

wherein R₁ is haioalkyl, or heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl™, alkyl, haioalkyl, or hydroxyl-alkyl-; R₃ is hydrogen, alky!, heterocyclyl, heteroaryl, heteroaryl-alkyl-, or cycioalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH₂-C(O)-, halo, or hydroxyl; R₄ is hydrogen; R₅ is hydrogen, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optica! isomers.

18. The compound of claim 17 wherein Ri is heterocyclyl that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxy!, alkoxy-alky!-, alky!, haioalkyl, or hydroxyl-alky!--,

19. The compound of claim 17 wherein R_t is 4- to 7-membered heterocyclyf that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxy!, (Ci-C₄)alkoxy-(CrC₄)aikyl-, {Ci-C₄)alkyi, (C-i- C₄)haloalkyl, or hydroxyl-(Ci-C₄)alkyi-; R₃ is hydrogen, (C₃-C₇)cycloalkyl, 4- to 7- membered heterocyclyl, or (CrC₄)alkyl that is optionally substituted by one halo group or one 5- to 6-membered heteroaryi group; R₄ and R₅ are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

20. The compound of claim 19 wherein Ri is pyrroiidinyl; R₃ is hydrogen, cyclopropyl, or (CrC₄)alkyl that is optionally substituted by one halo group or one 5- to 6-membered heteroaryi group; R₄ and R₅ are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

21. The compound of claim 19 wherein Ri is azetidinyl or 2-oxa-6- spiro[3,3]heptan-6-yl; R₃ is cyclopropyl; R₄ and R₅ are hydrogen; or a

pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

22. A method of treating a subject infected with RSV or prophylactic treatment of a subject susceptible to an RSV infection, comprising administering to the subject a therapeutically effective amount of the compound according to any of claims 1-21.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of according to any of claims 1-21 and one or more pharmaceutically acceptable carriers.

24. The pharmaceutical composition of claim 23 further comprising a second therapeutic agent.

25. The pharmaceutical composition of ciaim 24, wherein the second therapeutic agent is selected from the group consisting of an anti-inflammatory agent, an anti- viral agent and an anti-RSV agent.

26. A compound according to claims 1-21 or a pharmaceutically acceptable salt thereof for use in a method for the treatment of prophylactic treatment of an RSV infection.